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WO2023102659A1 - Dérivés de mescaline d'isopropylamine glycosylés et leurs méthodes d'utilisation - Google Patents

Dérivés de mescaline d'isopropylamine glycosylés et leurs méthodes d'utilisation Download PDF

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WO2023102659A1
WO2023102659A1 PCT/CA2022/051793 CA2022051793W WO2023102659A1 WO 2023102659 A1 WO2023102659 A1 WO 2023102659A1 CA 2022051793 W CA2022051793 W CA 2022051793W WO 2023102659 A1 WO2023102659 A1 WO 2023102659A1
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group
receptor
glycosyl
compound
chemical
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Jillian M. HAGEL
Jessica Bik-jing LEE
Peter J. Facchini
Chang-Chun LING
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Enveric Biosciences Canada Inc
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Enveric Biosciences Canada Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • compositions and methods disclosed herein relate to a chemical compound known as mescaline. Furthermore, the compositions and methods disclosed herein relate, to glycosylated derivatives of mescaline, including, in particular, isopropylamine analogues of mescaline derivatives.
  • Mescaline (chemical name 3,4,5 trimethoxyphenethylamine), for example, is a secondary metabolite that is naturally produced by certain cactus species belonging to a variety of genera within the plant family of Cactaceae.
  • Cactus species which can produce mescaline include, for example, cactus species belonging to the genus Lophophora, including Lophophora williamsii (peyote) and Lophophora diffusa and cactus species belonging to the genus Echinopsis/Trichocereus, including Echinopsis pachanoi/Trichocereus pachanoi (also known as San Pedro), Echinopsis peruviana/Trichocereus peruvianus (also known as Peruvian torch), (Echinopsis lageniformis/Trichocereus bridgesii/ (also known as Peruvian torch), and Echinopsis lageniformis/Trichocereus bridgesii/ (also known as Venezuelan torch), and
  • mescaline is a psychoactive compound and is therefore used as a recreational drug.
  • Mescaline is also used in Native American religious ceremonies, and for spiritual purposes by Andean indigenous cultures.
  • mescaline has been evaluated for its potential in the treatment of addictions, notably alcohol addiction (Bogenschutz, M.P. and Johnson M. W. (2016), Prog. in Neuro- Psychopharmacol. & Biol. Psychiatry 64; 250 - 258; Romeu, A.G. et al., (2017), Exp. Clin. Psychopharmacol.2016 Aug; 24(4): 229–268).
  • mescaline Although the toxicity of mescaline is low, adverse side effects, including, for example, panic attacks, paranoia, and psychotic states, sometimes together or individually referred to as “a bad trip”, are not infrequently experienced by mescaline users. Furthermore, mescaline can induce nausea and vomiting. [008] There exists therefore a need in the art for improved mescaline compounds. SUMMARY OF THE DISCLOSURE [009] The following paragraphs are intended to introduce the reader to the more detailed description, not to define or limit the claimed subject matter of the present disclosure. [0010] In one aspect, the present disclosure relates to mescaline and derivative compounds.
  • the present disclosure relates to isopropylamine analogues of glycosylated mescaline derivatives and methods of making and using these compounds.
  • the present disclosure provides, in at least one embodiment, in accordance with the teachings herein, a chemical compound having the chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1
  • one, two or three of X 1 , X 2 , and X 3 can be a glycosyl group.
  • one, two or three of X 1 , X 3 , and X 4 can be a glycosyl group.
  • one, two or three of X 1 , X 4 , and X 5 can be a glycosyl group.
  • one, two or three of X 1 , X 2 , and X 4 can be a glycosyl group.
  • one, two or three of X 1 , X 2 , and X 5 can be a glycosyl group.
  • one, two or three of X 2 , X 3 , and X 4 can be a glycosyl group.
  • one, two or three of X 2 , X 4 , and X 5 can be a glycosyl group.
  • one, two or three of X 3 , X 4 , and X 5 can be a glycosyl group.
  • one of X 1 or X 3 can be a glycosyl group, and the compound of formula (I) can possess a single glycosyl group.
  • one of X 1 or X 3 can be a glycosyl group, and two of X 2 , X 3 , and X 4 can be an O-alkyl group.
  • X 1 can be a glycosyl group, and X 2 and X 3 can be an O-alkyl group.
  • X 3 can be a glycosyl group
  • X 2 and X 4 can be an O-alkyl group.
  • the O-alkyl group can be independently or simultaneously selected from an O-(C 1 -C 6 )-alkyl group.
  • the O-alkyl group can be independently or simultaneously selected from an O-(C 1 -C 3 )-alkyl group.
  • the O-alkyl group can be a methoxy group (-OCH 3 ).
  • the compound of formula (I) when W is -N + (R 1 )(R 2 )(R 3 ), the compound of formula (I) can comprise a pharmaceutically acceptable anion.
  • the glycosyl group can be bonded in the furanose or pyranose form from its anomeric carbon atom.
  • the glycosyl group can be an O-linked glycosyl group.
  • the glycosyl group can be a C-linked glycosyl group.
  • the glycosyl group can be selected from a monosaccharide, disaccharide or trisaccharide. [0033] In at least one embodiment, in an aspect, the glycosyl group can be a polysaccharide including at least four saccharide groups. [0034] In at least one embodiment, in an aspect, the glycosyl group can be selected from a pentosyl group, a hexosyl group, and a heptosyl group.
  • the glycosyl group can be selected from a glucosyl group, a glucuronic acid group, a galactosyl group, a fucosyl group, a xylosyl group, an arabinosyl group, and a rhamnosyl group.
  • the glycosyl group can be selected from a glucosyl group, or a galactosyl group.
  • X 1 can be a glycosyl group
  • X 2 and X 3 can be an O-alkyl group
  • X 3 can be a glycosyl group
  • X 2 and X 4 can be an O-alkyl group, wherein the O-alkyl group can be independently or simultaneously selected from an O-(C 1 -C 6 )-alkyl group, and wherein the glycosyl group is selected from a glucosyl group, or a galactosyl group.
  • W can be -N(R 1 )(R 2 ), and R 1 can be a hydrogen atom, and R 2 can be an alkyl-aryl group.
  • W can be -N(R 1 )(R 2 ), and R 1 can each be an alkyl-aryl group.
  • the alkyl-aryl group can be a CH 2 -phenyl group or CH 2 -substituted phenyl group, wherein the phenyl group can be substituted with at least one halogen atom.
  • W can be -N(R 1 )(R 2 ), and R 1 can be a hydrogen atom, and R 2 can be an alkyl group.
  • W can be -N(R 1 )(R 2 ), and R 1 can each be a hydrogen atom.
  • the chemical compound having formula (I) can be selected from a compound having formula (IV) and (V): [0044]
  • the present disclosure relates to pharmaceutical and recreational drug formulations comprising glycosylated mescaline derivatives.
  • a pharmaceutical or recreational drug formulation comprising an effective amount of a chemical compound having the chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, or an
  • the present disclosure relates to methods of treatment of psychiatric disorders. Accordingly, the present disclosure further provides, in one embodiment, a method for treating a psychiatric disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a chemical compound having chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )
  • the disorder can be a 5- HT 2A receptor mediated disorder, or a 5-HT 1A receptor mediated disorder, or a 5- HT 2C receptor mediated disorder.
  • the disorder can be a 5- HT 1A receptor mediated disorder, wherein upon administration of an effective amount of the chemical compound to the subject, the chemical compound modulates a 5-HT 1A receptor, and does not modulate a 5-HT 2A receptor.
  • the disorder can be a 5- HT 1A receptor mediated disorder, wherein upon administration of an effective amount of the chemical compound to the subject, the chemical compound modulates a 5-HT 1A receptor and a 5-HT 2C receptor and does not modulate a 5- HT 2A receptor.
  • the disorder can be a 5- HT 2C receptor mediated disorder, wherein upon administration of an effective amount of the chemical compound to the subject, the chemical compound modulates a 5-HT 2C receptor, and does not modulate a 5-HT 2A receptor.
  • the disorder can be a 5- HT 2C receptor mediated disorder, wherein upon administration of an effective amount of the chemical compound to the subject, the chemical compound modulates the 5-HT 1A receptor, and the 5-HT 2C receptor, and does not modulate a 5-HT 2A receptor.
  • the disorder can be a 5- HT 2A receptor mediated disorder, wherein upon administration of an effective amount of the chemical compound to the subject, the chemical compound modulates a 5-HT 2A receptor, and does not modulate a 5-HT 1A receptor.
  • a dose can be administered of about 0.001 mg to about 5,000 mg.
  • the present disclosure provides, in at least one embodiment, a method for modulating a 5-HT 2A receptor or a 5-HT 1A receptor, the method comprising contacting the 5-HT 2A receptor or the 5-HT 1A receptor with a chemical compound having the chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i
  • the reaction conditions can be in vitro reaction conditions.
  • the reaction conditions can be in vivo reaction conditions.
  • the reaction conditions can be in vivo reaction conditions, and the in vivo reaction conditions comprise administering an effective amount of the chemical compound to a human or animal subject possessing a 5-HT 2A receptor and a 5-HT 1A receptor, wherein the 5-HT 1A receptor is modulated and the 5-HT 2A receptor is not modulated.
  • the reaction conditions can be in vivo reaction conditions, and the in vivo reaction conditions comprise administering an effective amount of the chemical compound to a human or animal subject possessing a 5-HT 2A receptor and a 5-HT 1A receptor, wherein the 5-HT 2A receptor is modulated and the 5-HT 1A receptor is not modulated.
  • the reaction conditions can be in vivo reaction conditions, and the in vivo reaction conditions comprise administering an effective amount of the chemical compound to a human or animal subject possessing a 5-HT 2A receptor, a 5-HT 1A receptor and a 5-HT 2C receptor, wherein the 5-HT 1A receptor and the 5-HT 2C receptor are modulated and the 5- HT 2A receptor is not modulated.
  • the present disclosure relates to methods of making glycosylated mescaline derivatives.
  • the present disclosure provides, in at least one embodiment, a method of making a glycosylated mescaline derivative having the chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, or an
  • the compound having formula (I) can be a compound having chemical formula (II) or (III): wherein O-Q is a glycosyloxy group, and wherein the method involves the performance of the chemical reactions selected from: (i) chemical reaction (e); (d) and (e); (c), (d) and (e); (b), (c), (d), and (e); or (a), (b), (c), (d), and (e), depicted in FIG.14A; or (ii) chemical reaction (j); (i) and (j); (h), (i) and (j); (g), (h), (i), and (j); or (f), (g), (h), (i), and (j), depicted in FIG.14B.
  • the compound having chemical formula (II) can have the chemical formula (IV): and the chemical reaction can be selected from the chemical reactions (e); (d) and (e); (c), (d) and (e); (b), (c), (d), and (e); or (a), (b), (c), (d), and (e), depicted in FIG.14A.
  • the compound having chemical formula (III) can have the chemical formula (V): and the chemical reaction can be selected from the chemical reactions (j); (i) and (j); (h), (i) and (j); (g), (h), (i), and (j); or (f), (g), (h), (i), and (j) depicted in FIG. 14B.
  • the present disclosure provides, in at least one embodiment, a method of making a glycosylated mescaline derivative having the chemical formula (XI): wherein, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are a hydrogen atom, a glycosyl group, or an O-alkyl group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are a hydrogen atom, and wherein one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 , and X 6 is an isopropylamino group (-CH 2 -CH(CH 3 )NH 2 ), the method comprising
  • the compound having formula (II) can be a compound having chemical formula (IV): [0066] In at least one embodiment, in an aspect, the compound having formula (III) can be a compound having chemical formula (V): [0067] In another aspect, the present disclosure relates to methods of making glycosylated mescaline derivatives in a host cell.
  • the present disclosure provides, in at least one embodiment, a method of making a glycosylated mescaline derivative the method comprising: (a) contacting an a hydroxy-containing mescaline derivative compound with a host cell comprising a glycosyl transferase, wherein the hydroxy- containing mescaline derivative compound has the chemical formula (XII): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O-alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a hydroxy group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 )(R 2 )
  • X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O-alkyl group, an O-acyl group, or a hydroxy group wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, or an alkyl-aryl group, wherein the aryl
  • the glycosyl transferase can be encoded by a nucleic acid selected from: (a) SEQ.ID NO: 1, SEQ.ID NO: 3, and SEQ.ID NO: 5; (b) a nucleic acid sequence that is substantially identical to any one of the nucleic acid sequences of (a); (c) a nucleic acid sequence that is substantially identical to any one of the nucleic acid sequences of (a) but for the degeneration of the genetic code; (d) a nucleic acid sequence that is complementary to any one of the nucleic acid sequences of (a); (e) a nucleic acid sequence encoding a polypeptide having any one of the amino acid sequences set forth in SEQ.ID NO: 2, SEQ.ID NO: 4, or SEQ.ID NO: 6; (f) a nucleic acid sequence that encodes a functional variant of any one of the amino acid sequences set forth in SEQ.ID NO: 2, SEQ.ID NO: 4,
  • the method can further include a step comprising isolating the glycosylated mescaline derivative compound.
  • the host cell can be a microbial cell.
  • the host cell can be a bacterial cell or a yeast cell.
  • the present disclosure provides, in at least one embodiment, a use of a chemical compound having chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, or an alkyl-aryl group, wherein
  • the manufacture can comprise formulating the chemical compound with an excipient, diluent or carrier.
  • the present disclosure provides, in at least one embodiment, a use of a chemical compound having chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R
  • FIG.1 depicts the chemical structure of mescaline and identifies a phenyl portion, comprising a substituted phenyl group, and an ethylamine portion of the chemical compound.
  • FIG.2 depicts a certain prototype structure of mescaline derivative compounds. The prototype structure contains a phenyl portion, comprising a substituted phenyl group, and an isopropylamine portion, as indicated. Certain carbon atoms may be referred to herein by reference to their position within the prototype structure, i.e., C 1 , C 2 , C 3 etc. The pertinent atom numbering is shown. Thus, for example, it will be clear from FIG.
  • isopropylamine chain extends from the C 1 carbon of the phenyl portion.
  • Mescaline derivatives comprising an isopropylamine side chain may be more specifically referred to herein as isopropylamine analogues of mescaline or mescaline derivatives, or as isopropylamine mescaline derivatives.
  • mescaline derivatives include various chemical compounds shown herein, such as the chemical compound having chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, or an alkyl-aryl group, wherein the aryl group
  • FIGS.3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M, 3N, 3O, 3P, 3Q, and 3R depict the chemical structures of certain example of mescaline derivatives, notably 3,4,5-X 2 ,X 3 ,X 4 isopropylamine mescaline derivatives (FIGS. 3A, 3B), 2,4,5-X 1 ,X 3 ,X 4 isopropylamine mescaline derivatives (FIGS. 3C, 3D), 2,3,4-X 1 ,X 2 ,X 3 isopropylamine mescaline derivatives (FIGS.
  • mescaline derivatives notably 3,4,5-X 2 ,X 3 ,X 4 isopropylamine mescaline derivatives (FIGS. 3A, 3B), 2,4,5-X 1 ,X 3 ,X 4 isopropylamine mescaline derivatives (FIGS. 3C, 3D),
  • one to three of each of X 1 , X 2 , X 3 , X 4 , and X 5 can be a glycosyl group, wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group can be an O-alkyl group, an O-acyl group, or a hydroxy group.
  • R 1 and R 2 can be an alkyl group, an acyl group, an alkyl-aryl group, wherein the aryl group is optionally substituted, or a hydrogen, atom, or R 1 and R 2 can be cyclized along with the nitrogen atom to which they are attached (FIGS.3A, 3C, 3E, 3G, 3I, 3K, 3M, 3O, 3Q), or (ii) R 1 , R 2 , and R 3 , can be an alkyl group, an acyl group, an alkyl- aryl group, wherein the aryl group is optionally substituted, or a hydrogen, atom, or R 1 and R 2 can be cyclized along with the nitrogen atom to which they are attached, and wherein the positively charged nitrogen atom in compound is balanced by Z-, a negatively charged anion (FIGS.3B, 3D, 3F, 3H, 3J, 3L, 3N, 3P, 3R).
  • FIGS.4A, 4B, 4C, 4D, 4E, 4F, and 4G depict the chemical structures of certain example mescaline derivatives, notably, a 2-glycosyloxy-4,6-X 3 ,X 5 isopropylamine mescaline derivative (FIG. 4A), a 4-glycosyloxy-X 1 ,X 5 isopropylamine mescaline derivative (FIG. 4B), a 6-glycosyloxy-2,4-X 1 ,X 3 mescaline derivative (FIG.
  • X 1 , X 2 , X 3 , X 4 , and X 5 can be an O-alkyl group, an O-acyl group, or a hydroxy group.
  • R 1 and R 2 can be an alkyl group, an acyl group, an alkyl-aryl group, wherein the aryl group is optionally substituted, or a hydrogen, atom, or R 1 and R 2 can be joined to form a heterocyclic ring along with the nitrogen atom to which they are attached.
  • FIGS.5A, 5B, 5C, 5D, 5E, and 5F depict the chemical structures of certain example mescaline derivatives, notably, a 4-glycosyloxy-2,6-dihydroxy isopropylamine mescaline derivative (FIG. 5A), a 4-glycosyloxy-2,6-methoxy isopropylamine mescaline derivative (FIG.
  • FIG. 5B a 4-glycosyloxy-2,6-acetoxy isopropylamine mescaline derivative
  • FIG. 5C a 4-glycosyloxy-2,6-acetoxy isopropylamine mescaline derivative
  • FIG. 5D a 2-ethoxy-4-glycosyloxy-6- hydroxy isopropylamine mescaline derivative
  • FIG. 5E a 2-hydroxy-4- glycosyloxy-6-propanoxy isopropylamine mescaline derivative
  • FIG. 5F 2- acetoxy-4-glycosyloxy-6-propanoxy isopropylamine mescaline derivative
  • R 1 and R 2 can be an alkyl group, an acyl group, an alkyl-aryl group, wherein the aryl group is optionally substituted, or a hydrogen, atom, or R 1 and R 2 can be joined to form a heterocyclic ring along with the nitrogen atom to which they are attached.
  • FIGS.6A, 6B, 6C, and 6D depict the chemical structures of certain example mescaline derivatives, notably, a 2-ethoxy-4-glycosyloxy-6-hydroxy isopropylamine mescaline derivative, wherein R 1 and R 2 , are hydrogen atoms, (FIG.
  • FIG. 6A a 2-ethoxy-4-glycosyloxy-6-hydroxy isopropylamine mescaline derivative, wherein R 1 and R 2 , are acetyl groups
  • FIG. 6B a 2-ethoxy-4- glycosyloxy-6-hydroxy isopropylamine mescaline derivative, wherein R 1 is a hydrogen atom and R 2 , is an acetyl group
  • FIG.6C a 2-ethoxy-4-glycosyloxy- 6-hydroxy isopropylamine mescaline derivative, wherein R 1 and R 2 are joined (along with the nitrogen atom to which they are attached) forming a piperidine group
  • FIGS.7A, 7B, 7C, and 7D depict the chemical structures of certain example mescaline derivatives, notably, a 2-ethoxy-4-glycosyloxy-6-hydroxy isopropylamine mescaline derivative, wherein R 1 , R 2 , and R 3 are hydrogen atoms, wherein the nitrogen atom is positively charged, and further including a negatively charged anion (Z-) balancing the positively charged nitrogen atom (FIG.7A), a 2- ethoxy-4-glycosyloxy-6-hydroxy isopropylamine mescaline derivative, wherein R 1 and R 2 are hydrogen atoms, R 3 is an acetyl group and further including a negatively charged anion (Z-) balancing the positively charged nitrogen atom (FIG.
  • FIGS.8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, and 8J depict the chemical structures of certain example mescaline derivatives, notably a 2-ethoxy-4- glycosyloxy-6-hydroxy isopropylamine mescaline derivative, wherein R 1 and R 2 are joined together (along with the nitrogen atom to which they are attached) forming a 6-membered heterocyclic ring wherein a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by an oxygen atom (to form a morpholinyl group), (FIG.
  • mescaline derivatives notably a 2-ethoxy-4- glycosyloxy-6-hydroxy isopropylamine mescaline derivative, wherein R 1 and R 2 are joined together (along with the nitrogen atom to which they are attached) forming a 6-membered heterocyclic ring wherein a carbon atom (together with its hydrogen atoms, relative to pipe
  • FIGS.9A, 9B, 9C, 9D, 9E, 9F, 9G, 9H, 9I, 9J, 9K, 9L, 9M, and 9N depict the chemical structures of certain example mescaline derivatives, notably a 3-glycosyl-4-hydroxy isopropylamine mescaline derivative (FIG.9A), a 2-glycosyl- 3,5-di-hydroxy isopropylamine mescaline derivative (FIG.9B), a 3,5-di-hydroxy-4- glycosyl isopropylamine mescaline derivative (FIG. 9C), a 2-glycosyl-3-hydroxy isopropylamine mescaline derivative (FIG.
  • FIGS.9A, 9B, 9C, 9D, 9E, 9F, 9G, 9H, 9I, 9J, 9K, 9L, 9M, and 9N depict the chemical structures of certain example mescaline derivatives, notably a 3-glycosyl-4-hydroxy isoprop
  • FIGS.10A, 10B, 10C, 10D, 10E, 10F, and 10G depict the chemical structures of certain example mescaline derivatives, notably, a 2-hydroxy-4,6- X 3 ,X 5 isopropylamine mescaline derivative (FIG. 10A), a 2,6-X 1 ,X 5 -4-hydroxy isopropylamine mescaline derivative (FIG.
  • X 1 , X 2 , X 3 , X 4 , and X 5 which are not a hydroxy group can be an O-alkyl group, or an O-acyl group.
  • R 1 and R 2 can be an alkyl group, an acyl group, or a hydrogen, atom, or R 1 and R 2 can be joined together, along with the nitrogen atom to which they are attached, to form a heterocyclic ring (see: FIG.3G).
  • FIGS. 11A and 11B depict example chemical reactions for synthesizing certain isopropylamine analogues of glycosylated mescaline derivatives.
  • FIG. 11A and 11B depict example chemical reactions for synthesizing certain isopropylamine analogues of glycosylated mescaline derivatives.
  • 11A depicts an example chemical reactions for synthesizing isopropylamine analogues of glycosylated mescaline derivative wherein the glycosyl group is bonded through its anomeric carbon atom and forming an O- linked glycosyl group notably a reaction wherein an isopropylamine analogue of a 4-hydroxy-mescaline derivative (11A-1) is reacted with benzyloxycarbonyl chloride to form an N-protected phenol intermediate (11A-2) that undergoes further a SN2 nucleophilic substitution with a tetra-per-O-benzylated glycosyl bromide (11A-3) to form the O-glycosyl compound (11A-4); subsequently all benzyl groups in compound (11A-4) can be removed under a catalytic hydrogenation to form an isopropylamine analogue of a 4-O-glycosyl-mescaline derivative (11A-5).
  • the free primary amino group of compound (11A-5) can be further N,N-dialkylated to from the corresponding isopropylamine analogue of a glycosylated tertiary mescaline amine derivative (11A-6) that can undergo another N-alkylation to form the corresponding isopropylamine analogue of a glycosylated mescaline ammonium derivative (11A-7).
  • FIG. 11B depicts example of chemical synthesis reactions wherein the glycosyl group is bonded through an anomeric carbon atom and forming a C-linked glycosyl group.
  • the highly activated 2-(1-chloropropan-2-yl)- 1,3,5-trimethoxybenzene (11B-1) is subjected to a glycosylation reaction with 1- O-acetyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose (11B-2) under the catalysis of boron trifluoride etherate, forming the corresponding 3-C-glycoside (11B-3) that contains a leaving group (Cl); subsequently, the primary chloride can be further displaced with either an N-substituted piperazine or a pyrrolidine to form isopropylamine analogues of 3-C-glycosylated mescaline derivatives (11B-4) and (11B-5), respectively.
  • FIG. 11C illustrates another example synthesis of another C- glycosylated isopropylamine analogue of a glycosylated mescaline derivative from 4-hydroxy-2,5-dimethoxybenzaldehyde (11C-1).
  • the 4-hydroxy functionality is first protected with a benzyl group to afford compound (11C-2), which undergoes a Henry condensation with nitroethane to provide the corresponding compound (11C-3).
  • a subsequent Lewis acid-catalyzed C-glycosylation with a 2,3,4,6-O-benzyl-O-acetyl-protected glycopyranose affords the 3-C-glycosylated intermediate compound (11C-8) which can be further deprotected using a catalytic hydrogenation condition to provide the desired isopropylamine analogue of 3-C- glycosyl-4-hydroxy-2,5-dimethoxy-mescaline derivative (11C-9).
  • FIGS.11D, 11E, and 11F show an enantioselective synthesis of both (R) and (S) enantiomers of isopropylamine analogues of glycosylated mescaline derivatives from 2-benzyloxy-1,3-dimethoxybenzene (11D-1).
  • a regioselective bromination affords compound (11D-2) which contains a 5-bromide which can be subsequently exchanged with a highly reactive lithium by reaction with n- butyllithium at low temperature (e.g., –70 oC).
  • the obtained highly nucleophilic compound (11D-3) can be subsequently reacted with either the N-Boc-protected (R)- or (S)-2-methylaziridine ((11D-4) or (11D-6)) to afford the corresponding (R)- or (S)-N-Boc-protected isopropylamine analogues of 2-benzyloxy-1,3- dimethoxymescaline derivatives (11D-5) and (11D-8), respectively.
  • the O-benzyl protecting group is removed from both substrates to provide the (R)- or (S)-enantiomer (11D-7) or (11E-1), respectively.
  • a subsequent Mitsunobu glycosylation with a 2,3,4,6-tetra-O-benzyl- glycopyranose (11E-2) affords the corresponding O-glycoside (11E-3) or (11F-1), respectively, using triphenylphosphine and diethyl azodicarboxylate (DEAD) as the reagents.
  • DEAD triphenylphosphine and diethyl azodicarboxylate
  • the N-Boc and all the O-benzyl protecting groups can be removed by a sequential catalytic hydrogenation and a treatment with trifluoroacetic acid to obtain intermediates (11E-4) or (11F-2), respectively.
  • FIG. 12 depicts an example chemical reaction for synthesizing an isopropylamine analogue of a glycosylated mescaline derivative, notably a reaction wherein an isopropylamine analogue of 4-hydroxy-mescaline derivative is reacted with a per-O-silylated glycosyl iodide compound under basic conditions followed by an acid-mediated O-desilylation to form an isopropylamine analogue of a 4-glycosyl-mescaline derivative.
  • FIG.13 depicts an example biochemical reaction for synthesizing an isopropyl analogue of a glycosylated mescaline derivative, notably an isopropylamine analogue of a 3-hydroxy-mescaline derivative is reacted with a UDP-glucose to form an isopropylamine analogue of a 3-glucose-mescaline derivative, in a reaction catalyzed by a glycosyl transferase.
  • FIGS. 14A and 14B depict example synthesis pathways and chemical reactions for making certain example mescaline derivative compounds of the present disclosure, including example isopropylamine mescaline derivative compounds (IV), and (V).
  • FIGS.15A, 15B, 15C, 15D, and 15E depict example reactions in an example chemical synthesis pathway for making a certain example compound according to the present disclosure, notably an example isopropylamine mescaline derivative compound having chemical formula (V).
  • FIGS. 16A, 16B, 16C, and 16D depict example reactions in an example chemical synthesis pathway for making certain example compound according to the present disclosure, notably an isopropylamine mescaline derivative compound having chemical formula (IV).
  • FIGS.17A (i), 17A (ii), 17B, 17C, 17D, 17E, 17F, 17G, 17H, 17I, 17J, 17K, and 17L depict various graphs representing certain experimental results, notably, graphs obtained in the performance of experimental assays to evaluate the efficacy of an example compound having chemical formula (V), notably, a cell viability assay (FIGS. 17A(i) and 17A(ii)); a radioligand 5-HT 1A receptor binding assay using 2C-B (positive control) (FIG.17B); a radioligand 5- HT 1A receptor binding assay using MDMA (positive control) (FIG.
  • FIG. 17C a radioligand 5-HT 1A receptor binding assay using mescaline (positive control) (FIG. 17D); a radioligand 5-HT 1A receptor binding assay using escaline (positive control) (FIG.17E); a radioligand 5-HT 1A receptor binding assay using proscaline (positive control) (FIG. 17F); a radioligand 5-HT 1A receptor binding assay using DMSO (negative control) (FIG.17G); a radioligand 5-HT 1A receptor binding assay using tryptophan (negative control) (FIG. 17H); a radioligand 5-HT 1A receptor binding assay using compound (V) (FIG.
  • FIGS.18A, 18B, and 18C depict various graphs representing certain experimental results, notably, graphs obtained in the performance of experimental assays to evaluate the efficacy of an example compound having chemical formula (IV), notably, a cell viability assay (FIG.
  • compositions, processes or systems having all of the features of any one composition, system or process described below or to features common to multiple or all of the compositions, systems or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter. Any subject matter disclosed in a composition, system or process described below that is not claimed in this document may be the subject matter of another protective instrument, for example, a continuing patent application, and the applicant(s), inventor(s) or owner(s) do not intend to abandon, disclaim or dedicate to the public any such subject matter by its disclosure in this document.
  • compositions, processes or systems having all of the features of any one composition, system or process described below or to features common to multiple or all of the compositions, systems or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter. Any subject matter disclosed in a composition, system or process described below that is not claimed in this document may be the subject matter of another protective instrument, for example, a continuing patent application, and the applicant(s), inventor(s) or owner(s) do not intend to abandon, disclaim or dedicate to the public any such subject matter by its disclosure in this document.
  • any range of values described herein is intended to specifically include the limiting values of the range, and any intermediate value or sub-range within the given range, and all such intermediate values and sub-ranges are individually and specifically disclosed (e.g., a range of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5).
  • other terms of degree such as “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of the modified term if this deviation would not negate the meaning of the term it modifies.
  • mecaline refers to a chemical compound having the structure set forth in FIG.1. It is noted that mescaline is also known in the art as 3,4,5 trimethoxyphenethylamine.
  • the term “mescaline derivative prototype structure” refers to a certain prototype chemical structure shown in FIG.2.
  • the mescaline derivatives disclosed herein include the mescaline derivative prototype structure shown in FIG.2, wherein various atoms may be substituted, as herein described. It is noted that the prototype structure comprises a phenyl portion and an isopropylamine portion (instead of an ethylamine portion as is the case for mescaline, see: FIG. 1). Furthermore, it is noted that specific carbon atoms in the mescaline derivative prototype structure are numbered. Reference may be made herein to these numbered carbons, for example, C 1 of the phenyl portion, C 2 of the phenyl portion.
  • hydroxy group refers to a molecule containing one atom of oxygen bonded to one atom of hydrogen and having the chemical formula -OH. A hydroxy group through its oxygen atom may be chemically bonded to another entity.
  • glycosylated refers to a saccharide group, such as a mono-, di-, tri- oligo- or a poly-saccharide group, which can be or has been bonded from its anomeric carbon either in the pyranose or furanose form, either in the ⁇ or the ⁇ conformation, or can be or has been bonded from a non-anomeric carbon atom, and can be in the pyranose or furanose form.
  • the saccharide group can be bonded via an oxygen atom to another entity, the bonded saccharide group, inclusive of the oxygen atom, may be referred to herein as a “glycosyloxy” group, and can be said to be “O-glycosylated” or “O- linked”.
  • glycosyl group includes glycosyloxy groups.
  • the saccharide group may also be bonded from a carbon atom and can then be said to be “C-glycosylated” or “C-linked”.
  • Example monosaccharide groups include, but are not limited to, a pentosyl, a hexosyl, or a heptosyl group.
  • glycosyl group may also be substituted with various groups. Such substitutions may include lower alkyl, lower alkoxy, acyl, carboxy, carboxyamino, amino, acetamido, halo, thio, nitro, keto, and phosphatyl groups, wherein the substitution may be at one or more positions on the saccharide. Included in the term glycosyl are further stereoisomers, optical isomers, anomers, and epimers of the glycosyl group.
  • a hexose group for example, can be either an aldose or a ketose group, can be of D- or L-configuration, can assume either an ⁇ - or ⁇ - conformation, and can be a dextro- or levo-rotatory with respect to plane-polarized light.
  • Example glycosyl groups further include, glucosyl group, glucuronic acid group, a galactosyl group, a fucosyl group, a xylosyl group, an arabinosyl group, and a rhamnosyl group.
  • alkyl group refers to a straight and/or branched chain, saturated alkyl radical containing from one to “p” carbon atoms (“C 1 -C p -alkyl”) and includes, depending on the identity of “p”, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, n-hexyl, and the like, where the variable p is an integer representing the largest number of carbon atoms in the alkyl radical.
  • Alkyl groups further include hydrocarbon groups arranged in a chain having the chemical formula -C n H 2n+1 , including, without limitation, methyl groups (-CH 3 ), ethyl groups (-C 2 H 5 ), propyl groups (-C 3 H 7 ), and butyl groups (-C 4 H 9 ).
  • the alkyl groups (including O-alkyl, and the alkyl groups present in acyl and O-acyl) in any of the embodiments of the disclosure is C 1 -C 20 -alkyl. In another embodiment, the alkyl group is C 1 -C 10 -alkyl. In another embodiment, the alkyl group is C 1 -C 6 -alkyl.
  • the alkyl group is C 1 -C 3 -alkyl. In another embodiment, the alkyl group is methyl, ethyl, propyl, butyl, or pentyl.
  • the term “O-alkyl group” refers to a hydrocarbon group arranged in a chain having the chemical formula -O-C n H 2n+1 .
  • Alkyl groups include (as defined above), without limitation, O-methyl groups (-O-CH 3 ), O-ethyl groups (-O-C 2 H 5 ), O-propyl groups (-O-C 3 H 7 ) and O-butyl groups (-O-C 4 H 9 ).
  • O-alkyl groups may also be referred to as alkoxy groups.
  • O- acyl groups may also be referred to as acyloxy groups.
  • aryl group refers to an aromatic ring compound in which at least one hydrogen compound has been removed from the aromatic ring to permit the bonding of a carbon atom in the aromatic ring to another entity.
  • the aryl groups can optionally be a substituted C 6 -C 14 -aryl.
  • the aryl group can further optionally be substituted C 6 -C 10 -aryl, or phenyl.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, or indenyl, and the like.
  • 5-HT 2A receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 5-HT 2A receptors can mediate a plurality of central and peripheral physiologic functions of serotonin. Central nervous system effects can include mediation of hallucinogenic effects of hallucinogenic compounds.
  • the term “modulating 5-HT 2A receptors”, as used herein, refers to the ability of a compound disclosed herein to alter the function of 5-HT 2A receptors.
  • a 5-HT 2A receptor modulator may activate the activity of a 5-HT 2A receptor, may activate or inhibit the activity of a 5-HT 2A receptor depending on the concentration of the compound exposed to the 5-HT 2A receptor, or may inhibit the activity of a 5- HT 2A receptor. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or maybe manifest only in particular cell types.
  • a 5-HT 2A receptor modulator may increase the probability that such a complex forms between the 5-HT 2A receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the 5-HT 2A receptor and the natural binding partner depending on the concentration of the compound exposed to the 5-HT 2A receptor, and or may decrease the probability that a complex forms between the 5-HT 2A receptor and the natural binding partner.
  • 5-HT 2A receptor-mediated disorder refers to a disorder that is characterized by abnormal 5-HT 2A receptor activity.
  • a 5-HT 2A receptor-mediated disorder may be completely or partially mediated by modulating 5-HT 2A receptors.
  • a 5-HT 2A receptor-mediated disorder is one in which modulation of 5-HT 2A receptors results in some effect on the underlying disorder e.g., administration of a 5-HT 2A receptor modulator results in some improvement in at least some of the subjects being treated.
  • 5-HT 1A receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HT 1A receptors can mediate a plurality of central and peripheral physiologic functions of serotonin. Ligand activity at 5-HT 1A is generally not associated with hallucination, although many hallucinogenic compounds are known to modulate 5-HT 1A receptors to impart complex physiological responses (Inserra et al., 2020, Pharmacol Rev 73: 202). [00117]
  • modulating 5-HT 1A receptors refers to the ability of a compound disclosed herein to alter the function of 5-HT 1A receptors.
  • a 5-HT 1A receptor modulator may activate the activity of a 5-HT 1A receptor, may activate or inhibit the activity of a 5-HT 1A receptor depending on the concentration of the compound exposed to the 5-HT 1A receptor, or may inhibit the activity of a 5- HT 1A receptor. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or maybe manifest only in particular cell types.
  • modulating 5-HT 1A receptors also refers to altering the function of a 5-HT 1A receptor by increasing or decreasing the probability that a complex forms between a 5-HT 1A receptor and a natural binding partner to form a multimer.
  • a 5-HT 1A receptor modulator may increase the probability that such a complex forms between the 5-HT 1A receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the 5-HT 1A receptor and the natural binding partner depending on the concentration of the compound exposed to the 5-HT 1A receptor, and or may decrease the probability that a complex forms between the 5-HT 1A receptor and the natural binding partner.
  • a 5-HT 1A receptor-mediated disorder may be completely or partially mediated by modulating 5-HT 1A receptors.
  • a 5-HT 1A receptor-mediated disorder is one in which modulation of 5-HT 1A receptors results in some effect on the underlying disorder e.g., administration of a 5-HT 1A receptor modulator results in some improvement in at least some of the subjects being treated.
  • the term “5-HT 2C receptor”, as used herein, refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 5-HT 2C receptors can mediate a plurality of central and peripheral physiologic functions of serotonin.
  • 5-HT2CRs 5-HT 2C ligands
  • modulating 5-HT 2C receptors refers to the ability of a compound disclosed herein to alter the function of 5-HT 2C receptors.
  • a 5-HT 2C receptor modulator may activate the activity of a 5-HT 2C receptor, may activate or inhibit the activity of a 5-HT 2C receptor depending on the concentration of the compound exposed to the 5-HT 2C receptor, or may inhibit the activity of a 5- HT 2C receptor. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or maybe manifest only in particular cell types.
  • modulating 5-HT 2C receptors also refers to altering the function of a 5-HT 2C receptor by increasing or decreasing the probability that a complex forms between a 5-HT 2C receptor and a natural binding partner to form a multimer.
  • a 5-HT 2C receptor modulator may increase the probability that such a complex forms between the 5-HT 2C receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the 5-HT 2C receptor and the natural binding partner depending on the concentration of the compound exposed to the 5-HT 2C receptor, and or may decrease the probability that a complex forms between the 5-HT 2C receptor and the natural binding partner.
  • a 5-HT 2C receptor-mediated disorder may be completely or partially mediated by modulating 5-HT 2C receptors.
  • a 5-HT 2C receptor-mediated disorder is one in which modulation of 5-HT 2C receptors results in some effect on the underlying disorder e.g., administration of a 5-HT 2C receptor modulator results in some improvement in at least some of the subjects being treated.
  • glycosyl transferase refers to any and all enzymes comprising a sequence of amino acid residues which is (i) substantially identical to the amino acid sequences constituting any glycosyl transferase polypeptide set forth herein, including, for example, SEQ.ID NO: 2, or (ii) encoded by a nucleic acid sequence capable of hybridizing under at least moderately stringent conditions to any nucleic acid sequence encoding any glycosyl transferase set forth herein, but for the use of synonymous codons.
  • nucleic acid sequence encoding a glycosyl transferase refers to any and all nucleic acid sequences encoding a glycosyl transferase polypeptide, including, for example, SEQ.ID NO: 1.
  • Nucleic acid sequences encoding a glycosyl transferase polypeptide further include any and all nucleic acid sequences which (i) encode polypeptides that are substantially identical to the glycosyl transferase polypeptide sequences set forth herein; or (ii) hybridize to any glycosyl transferase nucleic acid sequences set forth herein under at least moderately stringent hybridization conditions or which would hybridize thereto under at least moderately stringent conditions but for the use of synonymous codons.
  • nucleic acid refers to a sequence of nucleoside or nucleotide monomers, consisting of naturally occurring bases, sugars and intersugar (backbone) linkages. The term also includes modified or substituted sequences comprising non-naturally occurring monomers or portions thereof.
  • the nucleic acids of the present disclosure may be deoxyribonucleic nucleic acids (DNA) or ribonucleic acids (RNA) and may include naturally occurring bases including adenine, guanine, cytosine, thymidine, and uracil. The nucleic acids may also contain modified bases.
  • modified bases include aza and deaza adenine, guanine, cytosine, thymidine and uracil, and xanthine and hypoxanthine.
  • a sequence of nucleotide or nucleoside monomers may be referred to as a polynucleotide sequence, nucleic acid sequence, a nucleotide sequence, or a nucleoside sequence.
  • polypeptide refers to any and all polypeptides comprising a sequence of amino acid residues which is (i) substantially identical to the amino acid sequence constituting the polypeptide having such reference SEQ.ID NO, or (ii) encoded by a nucleic acid sequence capable of hybridizing under at least moderately stringent conditions to any nucleic acid sequence encoding the polypeptide having such reference SEQ.ID NO, but for the use of synonymous codons.
  • a sequence of amino acid residues may be referred to as an amino acid sequence, or polypeptide sequence.
  • nucleic acid sequence encoding a polypeptide refers to any and all nucleic acid sequences encoding a polypeptide having such reference SEQ.ID NO.
  • Nucleic acid sequences encoding a polypeptide, in conjunction with a reference SEQ.ID NO further include any and all nucleic acid sequences which (i) encode polypeptides that are substantially identical to the polypeptide having such reference SEQ.ID NO; or (ii) hybridize to any nucleic acid sequences encoding polypeptides having such reference SEQ.ID NO under at least moderately stringent hybridization conditions or which would hybridize thereto under at least moderately stringent conditions but for the use of synonymous codons.
  • substantially identical it is meant that two amino acid sequences preferably are at least 70% identical, and more preferably are at least 85% identical and most preferably at least 95% identical, for example 96%, 97%, 98% or 99% identical.
  • amino acid sequences of such two sequences are aligned, using for example the alignment method of Needleman and Wunsch (J. Mol. Biol., 1970, 48: 443), as revised by Smith and Waterman (Adv. Appl. Math., 1981, 2: 482) so that the highest order match is obtained between the two sequences and the number of identical amino acids is determined between the two sequences.
  • a particularly preferred method for determining the percentage identity between two polypeptides involves the Clustal W algorithm (Thompson, J D, Higgines, D G and Gibson T J, 1994, Nucleic Acid Res 22(22): 4673-4680 together with the BLOSUM 62 scoring matrix (Henikoff S & Henikoff, J G, 1992, Proc. Natl. Acad. Sci. USA 89: 10915-10919 using a gap opening penalty of 10 and a gap extension penalty of 0.1, so that the highest order match obtained between two sequences wherein at least 50% of the total length of one of the two sequences is involved in the alignment.
  • At least moderately stringent hybridization conditions it is meant that conditions are selected which promote selective hybridization between two complementary nucleic acid molecules in solution. Hybridization may occur to all or a portion of a nucleic acid sequence molecule. The hybridizing portion is typically at least 15 (e.g., 20, 25, 30, 40 or 50) nucleotides in length.
  • the parameters in the wash conditions that determine hybrid stability are sodium ion concentration and temperature.
  • a 1% mismatch may be assumed to result in about a 1° C. decrease in Tm, for example if nucleic acid molecules are sought that have a >95% identity, the final wash temperature will be reduced by about 5° C.
  • stringent hybridization conditions are selected.
  • Moderately stringent hybridization conditions include a washing step in 3 ⁇ SSC at 42° C. It is understood however that equivalent stringencies may be achieved using alternative buffers, salts, and temperatures.
  • polynucleotides or polypeptides refers to polynucleotides or polypeptides capable of performing the same function as a noted reference polynucleotide or polypeptide.
  • a functional variant of the polypeptide set forth in SEQ.ID NO: 2 refers to a polypeptide capable of performing the same function as the polypeptide set forth in SEQ.ID NO: 2.
  • Functional variants include modified a polypeptide wherein, relative to a noted reference polypeptide, the modification includes a substitution, deletion, or addition of one or more amino acids. In some embodiments, substitutions are those that result in a replacement of one amino acid with an amino acid having similar characteristics.
  • substitutions include, without limitation (i) glutamic acid and aspartic acid; (i) alanine, serine, and threonine; (iii) isoleucine, leucine, and valine, (iv) asparagine and glutamine, and (v) tryptophan, tyrosine, and phenylalanine.
  • Functional variants further include polypeptides having retained or exhibiting an enhanced mescaline or mescaline derivative biosynthetic bioactivity.
  • chimeric as used herein in the context of nucleic acids, refers to at least two linked nucleic acids which are not naturally linked. Chimeric nucleic acids include linked nucleic acids of different natural origins.
  • a nucleic acid constituting a microbial promoter linked to a nucleic acid encoding a plant polypeptide is considered chimeric.
  • Chimeric nucleic acids also may comprise nucleic acids of the same natural origin, provided they are not naturally linked.
  • a nucleic acid constituting a promoter obtained from a particular cell-type may be linked to a nucleic acid encoding a polypeptide obtained from that same cell-type, but not normally linked to the nucleic acid constituting the promoter.
  • Chimeric nucleic acids also include nucleic acids comprising any naturally occurring nucleic acids linked to any non-naturally occurring nucleic acids.
  • pharmaceutical formulation refers to a preparation in a form which allows an active ingredient, including a psychoactive ingredient, contained therein to provide effective treatment, and which does not contain any other ingredients which cause excessive toxicity, an allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • the pharmaceutical formulation may contain other pharmaceutical ingredients such as excipients, carriers, diluents, or auxiliary agents.
  • the term “recreational drug formulation”, as used herein, refers to a preparation in a form which allows a psychoactive ingredient contained therein to be effective for administration as a recreational drug, and which does not contain any other ingredients which cause excessive toxicity, an allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • the recreational drug formulation may contain other ingredients such as excipients, carriers, diluents, or auxiliary agents.
  • the term “effective for administration as a recreational drug”, as used herein, refers to a preparation in a form which allows a subject to voluntarily induce a psychoactive effect for non-medical purposes upon administration, generally in the form of self-administration.
  • the effect may include an altered state of consciousness, satisfaction, pleasure, euphoria, perceptual distortion, or hallucination.
  • the term “effective amount”, as used herein, refers to an amount of an active agent, pharmaceutical formulation, or recreational drug formulation, sufficient to induce a desired biological or therapeutic effect, including a prophylactic effect, and further including a psychoactive effect.
  • Such effect can include an effect with respect to the signs, symptoms or causes of a disorder, or disease or any other desired alteration of a biological system.
  • the effective amount can vary depending, for example, on the health condition, injury stage, disorder stage, or disease stage, weight, or sex of a subject being treated, timing of the administration, manner of the administration, age of the subject, and the like, all of which can be determined by those of skill in the art.
  • the terms “treating” and “treatment”, and the like, as used herein, are intended to mean obtaining a desirable physiological, pharmacological, or biological effect, and includes prophylactic and therapeutic treatment. The effect may result in the inhibition, attenuation, amelioration, or reversal of a sign, symptom or cause of a disorder, or disease, attributable to the disorder, or disease, which includes mental and psychiatric diseases and disorders.
  • Clinical evidence of the prevention or treatment may vary with the disorder, or disease, the subject, and the selected treatment.
  • pharmaceutically acceptable refers to materials, including excipients, carriers, diluents, or auxiliary agents, that are compatible with other materials in a pharmaceutical or recreational drug formulation and within the scope of reasonable medical judgement suitable for use in contact with a subject without excessive toxicity, allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • substantially pure and “isolated”, as may be used interchangeably herein describe a compound, e.g., a mescaline derivative, which has been separated from components that naturally accompany it.
  • a compound is substantially pure when at least 60%, more preferably at least 75%, more preferably at least 90%, 95%, 96%, 97%, or 98%, and most preferably at least 99% of the total material (by volume, by wet or dry weight, or by mole percent or mole fraction) in a sample is the compound of interest. Purity can be measured by any appropriate method, e.g., in the case of polypeptides, by chromatography, gel electrophoresis or HPLC analysis.
  • the present disclosure relates to mescaline derivatives, notably isopropylamine analogues of glycosylated mescaline derivatives (i.e., glycosylated isopropylamine mescaline derivatives).
  • the herein provided compositions exhibit functional properties which deviate from the functional properties of mescaline.
  • the glycosylated isopropylamine mescaline derivatives can exhibit pharmacological properties which deviate from mescaline, including for example with respect to in vivo or in vitro interaction with certain receptors, for example 5-HT 1A , 5-HT 2A , or 5- HT 2C receptors.
  • the glycosylated isopropylamine mescaline derivatives may exhibit physico-chemical properties which differ from mescaline.
  • the isopropylamine mescaline derivatives may exhibit superior solubility in a solvent, for example, an aqueous solvent.
  • the isopropylamine mescaline derivatives in this respect are useful in the formulation of pharmaceutical and recreational drug formulations.
  • the isopropylamine mescaline derivatives of the present disclosure can conveniently be biosynthetically produced. The practice of this method avoids the extraction of mescaline from cactus plants and the performance of subsequent chemical reactions to achieve the isopropylamine mescaline derivatives.
  • the present disclosure provides, in accordance with the teachings herein, in at least one embodiment, a chemical compound having chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R
  • X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O-alkyl group, an O-acyl group, or a hydroxy group.
  • X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group, or a hydrogen atom, are an O-alkyl group, an O-acyl group, or a hydroxy group.
  • W is either -N(R 1 )(R 2 ) or W is -N + (R 1 )(R 2 )(R 3 ), wherein (i) when W is -N(R 1 )(R 2 ), R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, an alkyl-aryl group, wherein the aryl group is optionally substituted, or R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or wherein (ii) when W is -N + (R 1 )(R 2 )(R 3 ), R 1 , R 2 and R 3 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, an alkyl-aryl group, wherein the aryl group is optionally substituted, or any two
  • X 1 , X 2 and X 3 can be one, two or three glycosyl groups.
  • one of X 1 , X 2 and X 3 can be a glycosyl group, and the two non-glycosylated substituents X 1 , X 2 and X 3 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 1 , X 2 and X 3 can be a glycosyl group, and the non- glycosylated substituent of X 1 , X 2 and X 3 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 1 , X 2 and X 3 can be glycosylated.
  • X 4 and X 5 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3E and 3F.
  • X 1 , X 3 and X 4 can be one, two or three glycosyl groups.
  • one of X 1 , X 3 and X 4 can be a glycosyl group, and the two non- glycosylated substituents X 1 , X 3 and X 4 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 1 , X 3 and X 4 can be a glycosyl group, and the non-glycosylated substituent of X 1 , X 3 and X 4 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 1 , X 3 and X 4 can be glycosylated.
  • X 2 and X 5 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3C and 3D.
  • X 1 , X 3 and X 5 can be one, two or three glycosyl groups.
  • one of X 1 , X 3 and X 5 can be a glycosyl group, and the two non- glycosylated substituents X 1 , X 3 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 1 , X 3 and X 5 can be a glycosyl group, and the non-glycosylated substituent of X 1 , X 3 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 1 , X 3 and X 5 can be glycosylated.
  • X 2 and X 4 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3G and 3H.
  • X 1 , X 2 and X 4 can be one, two or three glycosyl groups.
  • one of X 1 , X 2 and X 4 can be a glycosyl group, and the two non- glycosylated substituents X 1 , X 2 and X 4 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 1 , X 2 and X 4 can be a glycosyl group, and the non-glycosylated substituent of X 1 , X 3 and X 4 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 1 , X 2 and X 4 can be glycosylated.
  • X 3 and X 5 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3I and 3J.
  • X 1 , X 4 and X 5 can be one or two or three glycosyl groups.
  • one of X 1 , X 4 and X 5 can be a glycosyl group, and the two non- glycosylated substituents X 1 , X 4 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 1 , X 4 and X 5 can be a glycosyl group, and the non-glycosylated substituent of X 1 , X 4 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 1 , X 4 and X 5 can be glycosylated.
  • X 2 and X 3 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3K and 3L.
  • X 1 , X 2 and X 5 can be one or two or three glycosyl groups.
  • one of X 1 , X 2 and X 5 can be a glycosyl group, and the two non- glycosylated substituents X 1 , X 2 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 1 , X 2 and X 5 can be a glycosyl group, and the non-glycosylated substituent of X 1 , X 2 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 1 , X 2 and X 5 can be glycosylated.
  • X 3 and X 4 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3Q and 3R.
  • X 2 , X 3 and X 4 can be one or two or three glycosyl groups.
  • one of X 2 , X 3 and X 4 can be a glycosyl group, and the two non- glycosylated substituents X 2 , X 3 and X 4 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 2 , X 3 and X 4 can be a glycosyl group, and the non-glycosylated substituent of X 2 , X 3 and X 4 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 2 , X 3 and X 4 can be glycosylated.
  • X 1 and X 5 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3A and 3B.
  • X 2 , X 4 and X 5 can be one or two or three glycosyl groups.
  • one of X 2 , X 4 and X 5 can be a glycosyl group, and the two non- glycosylated substituents X 2 , X 4 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 2 , X 4 and X 5 can be a glycosyl group, and the non-glycosylated substituent of X 2 , X 4 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 2 , X 4 and X 5 can be glycosylated.
  • X 1 and X 3 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3M and 3N.
  • X 3 , X 4 and X 5 can be one or two or three glycosyl groups.
  • one of X 3 , X 4 and X 5 can be a glycosyl group, and the two non- glycosylated substituents X 3 , X 4 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or, in another embodiment, two of X 3 , X 4 and X 5 can be a glycosyl group, and the non-glycosylated substituent of X 3 , X 4 and X 5 can be O-alkyl group, an O-acyl group, or a hydroxy group; or in yet another embodiment, all three of X 3 , X 4 and X 5 can be glycosylated.
  • X 1 and X 2 are a hydrogen atom.
  • Example compounds in accordance with the foregoing embodiments are further shown in FIGS.3O and 3P.
  • Shown further in FIGS.4A – 4G are several example embodiments in according with the foregoing.
  • X 1 can be a glycosyl group (see: further also example isopropylamine mescaline derivative compound (V), herein).
  • X 3 and X 5 can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • X 2 and X 4 can be hydrogen atoms, and the mescaline derivative can be said to be an isopropylamine mescaline derivative .
  • X 3 can be a glycosyl group (see: further also example isopropylamine mescaline derivative compound (IV), herein).
  • X 1 and X 5 can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • X 2 and X 4 can be hydrogen atoms, and the mescaline derivative can be said to be an isopropylamine mescaline derivative.
  • X 5 can be a glycosyl group.
  • X 1 and X 3 can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • X 2 and X 4 can be hydrogen atoms, and the mescaline derivative can be said to be an isopropylamine mescaline derivative.
  • X 1 and X 3 can each be a glycosyl group.
  • X 5 can be selected from a hydroxy group, an O-alkyl group, or an O- acyl group.
  • X 2 and X 4 can be hydrogen atoms, and the mescaline derivative can be said to be an isopropylamine mescaline derivative.
  • X 1 and X 5 can each be a glycosyl group.
  • X 3 can be selected from a hydroxy group, an O-alkyl group, or an O- acyl group.
  • X 2 and X 4 can be hydrogen atoms, and the mescaline derivative can be said to be an isopropylamine mescaline derivative.
  • X 3 and X 5 can each be a glycosyl group.
  • X 1 can be a hydroxy group, an O-alkyl group, or an O-acyl group.
  • X 2 and X 4 can be hydrogen atoms, and the mescaline derivative can be said to be an isopropylamine mescaline derivative.
  • X 1 , X 3 and X 5 can each be a glycosyl group.
  • X 2 and X 4 can be hydrogen atoms, and the mescaline derivative can be said to be an isopropylamine mescaline derivative.
  • X 1 , X 3 and X 5 are substituents bonded to carbon atoms C 2 , C 4 and C 6 , respectively.
  • X 2 and X 4 are hydrogen atoms.
  • all of compounds shown in FIGS.4A – 4G correspond with the compound shown in FIG.3G. It is to be clearly understood, that, in this respect, FIGS. 4A – 4G represent example embodiments.
  • any one, any two, or all three of X 1 , X 2 , X 3 , X 4 , and X 5 can be glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group or a hydrogen atom, are independently selected from a hydroxy group atom, an O-alkyl group, or an O- acyl group.
  • the glycosyl groups in accordance with the present disclosure, can be any glycosyl group, including a mono-, di-, tri- oligo- or a poly-saccharide group, bonded from the anomeric carbon, either in the pyranose or furanose form, either in the ⁇ - or the ⁇ -conformation, or bonded from a non-anomeric carbon atom in either the furanose or pyranose form.
  • the glycosyl groups in accordance herewith may be O- linked glycosyl groups (i.e., glycosyloxy groups) or C-linked glycosyl groups.
  • the glycosyl group may also be substituted with various groups.
  • substitutions may include lower alkyl, lower alkoxy, acyl, carboxy, carboxyamino, amino, acetamido, halo, thio, nitro, keto, and phosphatyl groups. Such substitutions may be at one or more positions on the saccharide.
  • the glycosyl group may be a D-glucosyl group, D-fructosyl group, D-mannosyl group, D-ribosyl group, D-talosyl group, D- lyxosyl group, D-allosyl group, D-altrosyl group, D-gulosyl group, D-isosyl group, D-quinovosyl group, D-maltosyl group, D-cellobiosyl group, D-lactosyl group, D- maltotiosyl group, D-glucuronic acid group, D-galactosyl group, D-fucosyl group, D-xylosyl group, D-arabinosyl group, or a D-rhamnosyl group.
  • the glycosyl group may an L-glucosyl group, L-fructosyl group, L-mannosyl group, L-ribosyl group, L-talosyl group, L-lyxosyl group, L-allosyl group, L-altrosyl group, L-gulosyl group, L-isosyl group, L- quinovosyl group, L-maltosyl group, L-cellobiosyl group, L-lactosyl group, L- maltotiosyl group, L-glucuronic acid group, L-galactosyl group, L-fucosyl group, L- xylosyl group, L-arabinosyl group, or a L-rhamnosyl group.
  • the glycosyl group is a glycosyloxy group (i.e., a glycosyl group formed by bonding of the saccharide through its anomeric carbon atom).
  • the glycosyl group can be a glycosyloxy group selected from a glucosyloxy group, fructosyloxy group, mannosyoxy group, ribosyloxy group, talosyloxy group, lyxosyloxy group, allosyloxy group, altrosyloxy group, gulosyloxy group, isosyloxy group, quinovosyloxy group, maltosyloxy group, cellobiosyloxy group, lactosyloxy group, maltotiosyloxy group, glucuronicoxy acid group, galactosyloxy group, fucosyloxy group, xylosyloxy group, arabinosyloxy group, or a glycosyloxy group selected from a glucosyloxy group, fruct
  • the glycosyl groups are identical glycosyl groups (e.g., two glucosyl groups, two galactosyl groups, three galactosyl groups etc.). In other embodiments, the glycosyl groups may be different glycosyl groups (e.g., a glucosyl and a fucosyl group; a fucosyl group and a galactosyl group; a glucosyl group, a fucosyl group and a lactosyl group etc.).
  • the glycosyl groups may C-linked or O- linked. Examples of compounds comprising O-linked glycosyl groups in accordance herewith are shown in FIGS.4A – 4G, 5A – 5F, 6A – 6D, 7A – 7D, and 8A – 8J. Examples of compounds comprising C-linked glycosyl groups in accordance herewith are shown in FIGS.9A – 9N. [00173] Furthermore, in some embodiments, the chemical formula (I) may comprise at least one O-linked glycosyl group, and at least one C-linked glycosyl group.
  • substituent groups among X 1 , X 2 , X 3 , X 4 , and X 5 and continuing to refer to chemical formula (I), which are not glycosyl groups or hydrogen atoms, in an aspect hereof, as noted these substituent groups can be a hydroxy group, an O-alkyl group or an O-acyl group.
  • O-alkyl groups include, without limitation, methoxy groups (-OCH 3 ), ethoxy groups (-OC 2 H 5 ), propoxy groups (-OC 3 H 7 ) and butoxy groups (-OC 4 H 9 ).
  • Acyl groups include, without limitation, acetoxy groups (-OCOCH 3 ), propanoxy groups (-OCOCH 2 CH 3 ) and butanoxy groups (-OCOCH 2 CH 2 CH 3 ).
  • X 3 is a glycosyl group, and X 1 and X 5 are each a hydroxy group.
  • X 3 is a glycosyl group, and X 1 and X 5 are each a methoxy group.
  • X 3 is a glycosyl group, and X 3 and X 5 are each an acetoxy group.
  • X 3 is a glycosyl group, and X 1 is an ethoxy group, X 5 is a hydroxy group.
  • X 3 is a glycosyl group, and X 1 is a hydroxy group atom and X 5 is a propionate group.
  • X 3 is a glycosyl group, and X 1 is an acetoxy group and X 5 is a propanoxy group.
  • X 3 is a glycosyl group, and X 2 and X 4 are each a methoxy group.
  • X 1 is a glycosyl group, X 2 and X 3 are each a methoxy group.
  • X 1 , X 3 and X 5 are substituents bonded to carbon atoms C 2 , C 4 and C 6 , respectively.
  • X 2 and X 4 are hydrogen atoms.
  • the compounds shown in FIGS. 5A – 5F correspond with the compound shown in FIG.3G.
  • X 3 is a glycosyloxy group.
  • the compounds shown in FIGS.5A – 5F correspond with the compound shown in FIG.4B. It is to be clearly understood, that, in this respect, FIGS.
  • any one, any two, or three of X 1 , X 2 , X 3 , X 4 , and X 5 can be a glycosyloxy group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyloxy group or a hydrogen atom, can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • any one, any two, or three of X 1 , X 2 , X 3 , X 4 , and X 5 can be a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group or a hydrogen atom, can be independently selected from a hydroxy group, an O- alkyl group, or an O-acyl group.
  • W can be -N(R 1 )(R 2 ), and R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, an alkyl-aryl group, wherein the aryl group is optionally substituted, or R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or [00185]
  • R 1 and R 2 are each a hydrogen atom.
  • R 1 and R 2 are each an acetyl group.
  • R 1 is a hydrogen atom
  • R 2 is an acetyl group.
  • R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, and form a 6-member heterocyclic ring (piperidine ring).
  • W can be -N(R 1 )(R 2 ), and R 1 and/or and R 2 can be an alkyl-aryl group, for example a CH 2 -phenyl group, or substituted aryl group, or substituted CH 2 -phenyl group wherein the phenyl group is substituted with at least one halogen atom (Cl, F, Br, I).
  • R 1 or R 2 is an alkyl-aryl group
  • the remaining R 1 or R 2 can, for example, be a hydrogen atom or an alkyl group.
  • W can be -N + (R 1 )(R 2 )(R 3 ), and R 1 , R 2 and R 3 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, an alkyl-aryl group, wherein the aryl group is optionally substituted, or any two of R 1 , R 2 and R 3 are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • the nitrogen atom in compound (I) is positively charged, compound (I) further including a negatively charged anion balancing the positively charged nitrogen atom.
  • R 1 , R 2 , and R 3 are each a hydrogen atom. Furthermore, the nitrogen atom is positively charged, and compound (I) further includes a negatively charged anion balancing the positively charged nitrogen atom.
  • R 1 , and R 2 are each a hydrogen atom, and R 3 is an acetyl group. Furthermore, the nitrogen atom is positively charged, and compound (I) further includes a negatively charged anion balancing the positively charged nitrogen atom.
  • R 1 , and R 2 are each an acetyl group and R 3 is a hydrogen atom. Furthermore, the nitrogen atom is positively charged, and compound (I) further includes a negatively charged anion balancing the positively charged nitrogen atom.
  • R 1 and R 2 are joined to form a piperidine ring, and R 3 is a hydrogen atom. Furthermore, the nitrogen atom is positively charged, and compound (I) further includes a negatively charged anion balancing the positively charged nitrogen atom.
  • W can be -N + (R 1 )(R 2 )(R 3 ), and one, two or three, of R 1 R 2 and R 3 can be an alkyl-aryl group, for example a CH 2 - phenyl group, or substituted aryl group, or substituted CH 2 -phenyl group wherein the phenyl group is substituted with at least one halogen atom (Cl, F, Br, I).
  • the nitrogen atom is positively charged, and compound (I) further includes a negatively charged anion balancing the positively charged nitrogen atom.
  • R 1 , R 2 , or R 3 can, for example, be a hydrogen atom or an alkyl group.
  • the negatively charged anion can vary in different embodiments provided by the present disclosure, and includes a chloride ion (Cl-), a hydroxy ion (OH-), fluorine ion (F-), an iodine ion (I-), a sulfate ion (SO 4 2- ), or a phosphate ion (PO 4 3- ), for example.
  • X 1 , X 3 and X 5 are bonded to carbon atoms C 2 , C 4 and C 6 , respectively.
  • X 2 and X 4 are hydrogen atoms.
  • the compounds shown in FIGS.6A – 6D and 7A – 7D correspond with the compound shown in FIG.3G and FIG.3H, respectively.
  • X 3 is a glycosyloxy group.
  • the compounds shown in FIGS.6A – 6D and 7A – 7D correspond with the compound shown in FIG.4B. Furthermore, in the compounds shown in FIGS.6A – 6D and 7A – 7D X 1 is an ethoxy group and X 5 is a hydroxy group. In this respect, the compounds shown in FIGS.6A – 6D and 7A – 7D correspond with the compound shown in FIG. 5D. It is to be clearly understood, that, in this respect, the compounds shown in FIGS.6A – 6D and 7A – 7D represent example embodiments.
  • any one, any two, or three of X 1 , X 2 , X 3 , X 4 , and X 5 can be a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group or a hydrogen atom, can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • any one, any two, or three of X 1 , X 2 , X 3 , X 4 , and X 5 can be a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group or a hydrogen atom, can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • any one, any two, or three of X 1 , X 2 , X 3 , X 4 , and X 5 can be a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group or a hydrogen atom, can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • W can be -N + (R 1 )(R 2 )(R 3 ), and R 1 , R 2 and R 3 , and in some embodiments, any two of R 1 , R 2 and R 3 are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • the nitrogen atom in compound (I) is positively charged, compound (I) further including a negatively charged anion balancing the positively charged nitrogen atom.
  • R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, forming a 6- membered heterocyclic ring, a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by an oxygen atom.
  • R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, forming a 6- membered heterocyclic ring, a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a hydrogen atom.
  • R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, forming a 6- membered heterocyclic ring, a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a methyl group.
  • a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a methyl group.
  • the methyl group represents an example of an alkyl group.
  • the nitrogen atom may be bonded to other alkyl groups.
  • R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, forming a 6- membered heterocyclic ring, a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to an acetyl group.
  • the acetyl group represents an example of an acyl group.
  • the nitrogen atom may be bonded to other acyl groups.
  • R 3 is a hydrogen atom
  • the compound further includes a negatively charged anion (Z-) balancing the positively charged nitrogen atom.
  • Z- negatively charged anion
  • Example embodiments in this respect are shown in FIGS.8F – 8J.
  • the negatively charged anion can vary in different embodiments, and includes a chloride ion (Cl-), a hydroxy ion (OH-), fluorine ion (F-), an iodine ion (I-), a sulfate ion (SO 4 2- ), or a phosphate ion (PO 4 3- ), for example.
  • R 1 and R 2 are joined forming a 6-membered heterocyclic ring
  • a first carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom
  • the nitrogen atom and a second carbon atom are further joined to form a 5-membered heterocyclic ring
  • R 3 is a hydrogen atom and further including a negatively charged anion (Z-) balancing the positively charged nitrogen atom.
  • the 5- membered heterocyclic group represents an example of a bicyclic heterocyclic ring.
  • the nitrogen atom may be bonded to form other bicyclic heterocyclic rings.
  • the glycosylated mescaline derivative can be a compound having formula (IV): [00211]
  • the glycosylated mescaline derivative can be a compound having formula (V): [00212]
  • the glycosylated mescaline derivatives of the present disclosure include salts thereof, including pharmaceutically acceptable salts.
  • the nitrogen atom of the ethyl-amino group extending in turn from the C 1 atom may be protonated, and the positive charge may be balanced by, for example, chloride or sulfate ions, to thereby form a chloride salt or a sulfate salt.
  • the compound having chemical formula (I) may be in the (S)-enantiomeric form in accordance with chemical formula (XIII): [00214] In other embodiments, the compound having chemical formula (I) may be in the (R)-enantiomeric form in accordance with chemical formula (XIV): [00215] Synthesis methods for the (S)- and (R)-enantiomeric forms are hereinafter discussed with reference to FIG.11D. [00216] Thus, to briefly recap, the present disclosure provides glycosylated mescaline derivatives.
  • the present disclosure provides in a particular a chemical compound having formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, or an alkyl-aryl group, wherein the aryl group is optionally substituted, or R 1 and
  • a glycosyl group including a glycosyloxy group
  • a (C 1 -C 20 )-alkyl group a -O-(C 1 -C 20 )-alkyl group
  • a hydroxy group
  • a glycosyl group including a glycosyloxy group
  • a (C 1 -C 10 )-alkyl group a -O-(C 1 -C 10 )-alkyl group
  • a hydroxy group
  • a glycosyl group including a glycosyloxy group
  • X 1 , X 2 , X 3 , X 4 , and X 5 can be independently or simultaneously a hydrogen atom, a glycosyl group (including a glycosyloxy group), a (C 1 -C 3 )-alkyl group (-CH 2 -CH 2 -CH 3 (propyl); -CH 2 -CH 3 (ethyl); or -CH 3 (methyl)), a -O-(C 1 -C 3 )-alkyl group (-OC 3 H 7 (O-propyl; propoxy); -OC 2 H 5 (O-ethyl; ethoxy); or -OCH 3 (O-methyl; methoxy), a (C 1 -C 3 )-O-acyl group (e.g.
  • R 1 , R 2 , or R 3 can be independently or simultaneously an alkyl group, (C 1 -C 20 )-alkyl group, (C 1 -C 10 )-alkyl group, (C 1 -C 6 )- alkyl group, or (C 1 -C 3 )-alkyl group (-CH 2 -CH 2 -CH 3 (propyl); -CH 2 -CH 3 (ethyl); or - CH 3 (methyl)).
  • R 1 , R 2 , and R 3 can be independently or simultaneously an acyl group, (C 1 -C 20 )-acyl group (e.g.
  • R 1 , R 2 , and R 3 can be independently or simultaneously a (C 1 -C 20 )-alkyl-aryl group, (C 1 -C 10 )-alkyl-aryl group, a (C 1 -C 6 )- alkyl-aryl group, (C 1 -C 3 )-alkyl-aryl group, for example, a C 1 -alkyl-aryl group, (-CH 2 - phenyl; -CH 2 -naphthyl, -CH 2 -tetrahydronaphthyl; -CH 2 -indanyl etc.); or a C 2 -alkyl- aryl group (-CH 2 -CH 2 -phenyl; -CH 2 -CH 2 -naphthyl; -CH 2 -CH 2 -tetrahydronaphthyl; - CH 2 -CH 2 -ind
  • the aryl group can optionally be substituted including, for example, with one or more halogens (Cl, F, Br, I), one or more alkyl group ((C 1 -C 20 )-alkyl group, (C 1 - C 10 )-alkyl group, (C 1 -C 6 )-alkyl group, or (C 1 -C 3 )-alkyl group (-CH 2 -CH 2 -CH 3 (propyl); -CH 2 -CH 3 (ethyl); or -CH 3 (methyl)), or an O-alkyl group -O-(C 1 -C 20 )-alkyl group, -O-(C 1 -C 10 )-alkyl group, -O-(C 1 -C 6 )-alkyl group, one or more -O-(C 1 -C 3 )- alkyl group (-OC 3 H 7 (
  • any two of R 1 , R 2 , and R 3 can be a joined together to form a 3-10-membered heterocyclic ring, a 3-9-membered heterocyclic ring, or a 3-6-membered heterocyclic ring, or a 5-6-membered ring.
  • the compound of formula (I) X 1 or X 3 can be a glycosyl group, and the compound of formula (I) can have a single glycosyl group.
  • the compound of formula (I) can possess a single glycosyl group, and X 1 or X 3 can be a glycosyl group, and two of X 2 , X 3 , and X 4 can be an O-alkyl group.
  • the compound of formula (I) can possess a single glycosyl group, and X 1 can be a glycosyl group, and X 2 and X 3 can be an O-alkyl group.
  • the compound of formula (I) can possess a single glycosyl group, and X 3 can be a glycosyl group, and X 2 and X 4 can be an O-alkyl group.
  • the O-alkyl group can be independently or simultaneously selected from an O-(C 1 -C 6 )-alkyl group, an O-(C 1 -C 3 )-alkyl group, or a methoxy group (OCH 3 ).
  • the glycosylated mescaline derivatives of the present disclosure may be used to prepare a pharmaceutical or recreational drug formulation.
  • the present disclosure further provides in another aspect, pharmaceutical and recreational drug formulations comprising glycosylated isopropylamine mescaline derivatives.
  • the present disclosure provides in a further embodiment a pharmaceutical or recreational drug formulation comprising a chemical compound having chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, an acyl group, or an alkyl-aryl group,
  • the dose when using the compounds of the present disclosure can vary within wide limits, and as is customary and is known to those of skill in the art, the dose can be tailored to the individual conditions in each individual case.
  • the dose depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated, or prophylaxis is conducted, on the mode of delivery of the compound, or on whether further active compounds are administered in addition to the compounds of the present disclosure.
  • Representative doses of the present invention include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to about 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg.
  • Representative doses of the present disclosure include, but are not limited to, about 0.0001 to about 1,000 mg, about 10 to about 160 mg, about 10 mg, about 20 mg, about 40 mg, about 80 mg or about 160 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4, doses.
  • the pharmaceutical or recreational drug formulations may be prepared as liquids, tablets, capsules, microcapsules, nanocapsules, trans-dermal patches, gels, foams, oils, aerosols, nanoparticulates, powders, creams, emulsions, micellar systems, films, sprays, ovules, infusions, teas, decoctions, suppositories, etc. and include a pharmaceutically acceptable salt or solvate of the glycosylated mescaline derivative compound together with an excipient.
  • excipient means any ingredient other than the chemical compound of the disclosure.
  • excipient may depend on factors such as the particular mode of administration, the effect of the excipient on solubility of the chemical compounds of the present disclosure and methods for their preparation will be readily apparent to those skilled in the art.
  • Such compositions and methods for their preparation may be found, for example, in “Remington's Pharmaceutical Sciences”, 22nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at the University of the Sciences, 2012).
  • the pharmaceutical and drug formulations comprising the glycosylated mescaline derivatives of the present disclosure may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include both solid and liquid formulations.
  • Solid formulations include tablets, capsules (containing particulates, liquids, microcapsules, or powders), lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomal preparations, microencapsulated preparations, creams, films, ovules, suppositories, and sprays.
  • Liquid formulations include suspensions, solutions, syrups, and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80. When present, surface active agents may comprise from 0.2% (w/w) to 5% (w/w) of the tablet.
  • Tablets may further contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25% (w/w) to 10% (w/w), from 0.5% (w/w) to 3% (w/w) of the tablet.
  • tablets may contain a disintegrant.
  • disintegrants examples include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 % (w/w) to 25% (w/w) or from 5% (w/w) to 20% (w/w) of the dosage form.
  • Other possible auxiliary ingredients include anti-oxidants, colourants, flavouring agents, preservatives, and taste-masking agents.
  • the chemical compound of the present disclosure may make up from 1% (w/w) to 80 % (w/w) of the dosage form, more typically from 5% (w/w) to 60% (w/w) of the dosage form.
  • Exemplary tablets contain up to about 80% (w/w) of the chemical compound, from about 10% (w/w) to about 90% (w/w) binder, from about 0% (w/w) to about 85% (w/w) diluent, from about 2% (w/w) to about 10% (w/w) disintegrant, and from about 0.25% (w/w) to about 10% (w/w) lubricant.
  • the formulation of tablets is discussed in “Pharmaceutical Dosage Forms: Tablets”, Vol.1 – Vol.3, by CRC Press (2008).
  • the pharmaceutical and recreational drug formulations comprising the glycosylated isopropylamine mescaline derivatives of the present disclosure may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • the pharmaceutical and recreational drug formulations can be administered parenterally (for example, by subcutaneous, intravenous, intraarterial, intrathecal, intraventricular, intracranial, intramuscular, or intraperitoneal injection).
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffering agents (in one embodiment, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile water.
  • Formulations comprising the glycosylated isopropylamine mescaline derivatives of the present disclosure for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the chemical compounds of the disclosure may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(dl-lactic-coglycolic)acid
  • the pharmaceutical or recreational drug formulations of the present disclosure also may be administered topically to the skin or mucosa, i.e., dermally, or transdermally.
  • Example pharmaceutical and recreational drug formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, cosmetics, oils, eye drops, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Example carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporate (see: for example, Finnin, B. and Morgan, T.M., 1999 J. Pharm. Sci, 88 (10), 955-958).
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid pharmaceutical compositions can contain suitable pharmaceutically acceptable excipients.
  • the pharmaceutical compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Pharmaceutical compositions in pharmaceutically acceptable solvents can be nebulized by use of inert gases.
  • Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder pharmaceutical compositions can be administered, e.g., orally, or nasally, from devices that deliver the formulation in an appropriate manner.
  • the glycosylated isopropylamine mescaline compounds of present disclosure are used as a recreational drug
  • the compounds may be included in compositions such as a food or food product, a beverage, a food seasoning, a personal care product, such as a cosmetic, perfume or bath oil, or oils (both for topical administration as massage oil, or to be burned or aerosolized).
  • the chemical compounds of the present disclosure may also be included in a “vape” product, which may also include other drugs, such as nicotine, and flavorings.
  • a “vape” product which may also include other drugs, such as nicotine, and flavorings.
  • the pharmaceutical formulations comprising the chemical compounds of the present disclosure may be used to treat a subject, and, in particular, to treat a psychiatric disorder in a subject.
  • the present disclosure includes in a further embodiment, a method for treating a psychiatric disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a chemical compound having chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, an
  • Psychiatric disorders that may be treated include, for example, neurodevelopmental disorders such as intellectual disability, global development delay, communication disorders, autism spectrum disorder, and attention-deficit hyperactivity disorder (ADHD); bipolar and related disorders, such as mania, and depressive episodes; anxiety disorder, such as generalized anxiety disorder (GAD), agoraphobia, social anxiety disorder, specific phobias (natural events, medical, animal, situational, for example), panic disorder, and separation anxiety disorder; stress disorders, such as acute stress disorder, adjustment disorders, post-traumatic stress disorder (PTSD), and reactive attachment disorder; dissociative disorders, such as dissociative amnesia, dissociative identity disorder, and depersonalization/derealization disorder; somatoform disorders, such as somatic symptom disorders, illness anxiety disorder, conversion disorder, and factitious disorder; eating disorders, such as anorexia nervosa, bulimia nervosa, rumination disorder, pica, and binge-eating disorder; sleep disorders, such as narcolepsy, insomnia
  • substance-related disorders such as alcohol-related disorders, cannabis related disorders, inhalant-use related disorders, stimulant use disorders, and tobacco use disorders
  • neurocognitive disorders such as delirium; schizophrenia; compulsive disorders, such as obsessive compulsive disorders (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania disorder, excoriation disorder, substance/medication induced obsessive- compulsive disorder, and obsessive-compulsive disorder related to another medical condition
  • personality disorders such as antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder.
  • the compounds of the present disclosure may be used to be contacted with a 5-HT 2A receptor to thereby modulate the 5-HT 2A receptor.
  • Such contacting includes bringing a compound of the present disclosure and 5- HT 2A receptor together under in vitro conditions, for example, by introducing the compounds in a sample containing a 5-HT 2A receptor, for example, a sample containing purified 5-HT 2A receptors, or a sample containing cells comprising 5- HT 2A receptors.
  • In vitro conditions further include the conditions described in Examples 1 and 2 hereof.
  • Contacting further includes bringing a compound of the present disclosure and 5-HT 2A receptor together under in vivo conditions.
  • Such in vivo conditions include the administration to an animal or human subject, for example, of a pharmaceutically effective amount of the compound of the present disclosure, when the compound is formulated together with a pharmaceutically active carrier, diluent, or excipient, as hereinbefore described, to thereby treat the subject.
  • the compound may activate the 5-HT 2A receptor or inhibit the 5-HT 2A receptor.
  • the reaction conditions can be in vivo reaction conditions, and the in vivo reaction conditions can comprise administering an effective amount of the chemical compound to a human or animal subject possessing a 5-HT 1A receptor and a 5-HT 2A receptor, wherein the 5-HT 2A receptor is modulated, and wherein at the same time the 5-HT 1A receptor is not modulated, or substantially modulated.
  • compound (IV) set forth herein when administered to a subject may modulate the 5-HT 2A receptor, and at the same time not modulate the 5-HT 1A receptor.
  • the condition that may be treated in accordance herewith can be any 5-HT 2A receptor mediated disorder.
  • disorders include, but are not limited to schizophrenia, psychotic disorder, attention deficit hyperactivity disorder, autism, and bipolar disorder.
  • the disorder can be a 5-HT 2A receptor mediated disorder, wherein upon administration of the chemical compound to the subject, the chemical compound modulates a 5-HT 2A receptor, without however modulating, or substantially modulating, a 5-HT 1A receptor in the subject.
  • the compounds of the present disclosure may be used to be contacted with a 5-HT 1A receptor to thereby modulate the 5-HT 1A receptor.
  • Such contacting includes bringing a compound of the present disclosure and 5- HT 1A receptor together under in vitro conditions, for example, by introducing the compounds in a sample containing a 5-HT 1A receptor, for example, a sample containing purified 5-HT 1A receptors, or a sample containing cells comprising 5- HT 1A receptors.
  • In vitro conditions further include the conditions described in Examples 1 and 2 hereof.
  • Contacting further includes bringing a compound of the present disclosure and 5-HT 1A receptor together under in vivo conditions.
  • Such in vivo conditions include the administration to an animal or human subject, for example, of a pharmaceutically effective amount of the compound of the present disclosure, when the compound is formulated together with a pharmaceutically active carrier, diluent, or excipient, as hereinbefore described, to thereby treat the subject.
  • the compound may activate the 5-HT 1A receptor or inhibit the 5-HT 1A receptor.
  • the reaction conditions can be in vivo reaction conditions, and the in vivo reaction conditions can comprise administering an effective amount of the chemical compound to a human or animal subject possessing a 5-HT 1A receptor and a 5-HT 2A receptor, wherein the 5-HT 1A receptor is modulated, and wherein at the same time the 5-HT 2A receptor is not modulated, or substantially modulated.
  • compound (V) set forth herein when administered to a subject may modulate the 5-HT 1A receptor, and at the same time not modulate the 5-HT 2A receptor.
  • the reaction conditions can be in vivo reaction conditions, and the in vivo reaction conditions can comprise administering an effective amount of the chemical compound to a human or animal subject possessing a 5-HT 1A receptor, a 5-HT 2A receptor, and a 5-HT 2C receptor wherein the 5-HT 1A receptor and 5-HT 2C are modulated, and wherein at the same time the 5-HT 2A receptor is not modulated, or substantially modulated.
  • compound (V) set forth herein when administered to a subject may modulate the 5-HT 1A receptor and the 5-HT 2C receptor, and at the same time not modulate the 5-HT 2A receptor.
  • the condition that may be treated in accordance herewith can be any 5-HT 1A receptor mediated disorder.
  • Such disorders include, but are not limited to schizophrenia, psychotic disorder, attention deficit hyperactivity disorder, autism, and bipolar disorder.
  • the disorder can be a 5-HT 1A receptor mediated disorder, wherein upon administration of the chemical compound to the subject, the chemical compound modulates a 5-HT 1A receptor, without however modulating, or substantially modulating, a 5-HT 2A receptor in the subject.
  • the disorder can be a 5-HT 1A receptor mediated disorder, wherein upon administration of the chemical compound to the subject, the chemical compound modulates a 5-HT 1A receptor and a 5-HT 2C receptor, without however modulating, or substantially modulating, a 5-HT 2A receptor in the subject.
  • the compounds of the present disclosure may be used to be contacted with a 5-HT 2C receptor to thereby modulate the 5-HT 2C receptor.
  • Such contacting includes bringing a compound of the present disclosure and 5- HT 2C receptor together under in vitro conditions, for example, by introducing the compounds in a sample containing a 5-HT 2C receptor, for example, a sample containing purified 5-HT 2C receptors, or a sample containing cells comprising 5- HT 2C receptors.
  • In vitro conditions further include the conditions described in Examples 1 and 2 hereof.
  • Contacting further includes bringing a compound of the present disclosure and 5-HT 2C receptor together under in vivo conditions.
  • Such in vivo conditions include the administration to an animal or human subject, for example, of a pharmaceutically effective amount of the compound of the present disclosure, when the compound is formulated together with a pharmaceutically active carrier, diluent, or excipient, as hereinbefore described, to thereby treat the subject.
  • the compound may activate the 5-HT 2C receptor or inhibit the 5-HT 2C receptor.
  • the condition that may be treated in accordance herewith can be any 5-HT 2C receptor mediated disorder.
  • the disorder can be a 5-HT 2C receptor mediated disorder, wherein upon administration of the chemical compound to the subject, the chemical compound modulates a 5-HT 2C receptor, without however modulating, or substantially modulating, a 5-HT 2A receptor in the subject.
  • the disorder can be a 5-HT 2C receptor mediated disorder, wherein upon administration of the chemical compound to the subject, the chemical compound modulates a 5-HT 1A receptor and a 5-HT 2C receptor, without however modulating, or substantially modulating, a 5-HT 2A receptor in the subject.
  • the glycosylated isopropylamine mescaline derivatives of the present disclosure may be prepared in any suitable manner, including by any organic chemical synthesis methods, biosynthetic methods, or a combination thereof.
  • One suitable method of to making the glycosylated isopropyl mescaline derivatives of the present disclosure initially involves selecting and obtaining or preparing a hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide-containing mescaline derivative compound and a glycosyl compound and reacting the hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide- containing mescaline derivative compound and a glycosyl compound to obtain the glycosyl mescaline derivatives of the present disclosure.
  • Suitable hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide-containing mescaline derivative compounds include compounds comprising the prototype structure shown in FIG.2, including, for example, the hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide-containing containing mescaline derivative having the formula (II): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a hydroxy group, alkoxy group, acyloxy group, alkyl group, amino group, acylamino group, or a halide, wherein two of X
  • one, two, or three of X 1 , X 2 , X 3 , X 4 , and X 5 can be a hydroxy group, an alkoxy group, an acyloxy group, an alkyl group, an amino group, an acylamino group, or a halide.
  • the hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide- containing mescaline derivative compounds may be provided in a more or less chemically pure form, for example, in the form of a hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide-containing mescaline derivative preparation having a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9%.
  • glycosyl compounds of the present disclosure in general, in accordance herewith any glycosyl compound may be selected, obtained, or prepared and used.
  • Suitable glycosyl compounds include, for example, hexosyl or pentosyl compounds. Further suitable compounds include monosaccharides, disaccharides, trisaccharides, and polysaccharides.
  • glycosyl compounds which may be selected are glucose and glucosyl containing compounds and glucose and glucosyl derivatives, such as uridine diphosphate glucose (UDP-glucose), including D- and L-glucose and glucosyl derivatives.
  • UDP-glucose uridine diphosphate glucose
  • glycosyl compounds which may be selected are glucuronic acid and glucuronic acid containing compounds and glucuronic acid derivatives thereof, including D- and L-glucuronic acid and glucuronic derivatives.
  • glycosyl compounds which may be selected are galactose and galactosyl, and galactose and galactosyl containing compounds and galactose and galactosyl derivatives, such as uridine diphosphate galactose (UDP-galactose), including D- and L-galactose and galactosyl derivatives.
  • UDP-galactose uridine diphosphate galactose
  • glycosyl compounds which may be selected are fucose and fucosyl containing compounds and fucose and fucosyl derivatives, including D- and L-fucose and fucosyl derivatives.
  • glycosyl compounds which may be selected are xylose and xylosyl containing compounds and xylose and xylosyl and derivatives, including D- and L-xylose and xylosyl derivatives.
  • glycosyl compounds which may be selected are arabinose and arabinosyl containing compounds and arabinose and arabinosyl derivatives, including D- and L- arabinose and arabinosyl derivatives.
  • glycosyl compounds which may be selected are rhamnose and rhamnosyl containing compounds and rhamnose and rhamnosyl derivatives, including D- and L-rhamnose and rhamnosyl derivatives.
  • the glycosyl compound may be provided in a more or less chemically pure form, for example, in the form of a glycosyl compound preparation having a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9%.
  • the glycosyl compound may be chemically synthesized or obtained from a fine chemical manufacturer.
  • a hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide-containing mescaline derivative and a glycosyl compound are provided, and the hydroxy-, alkoxy-, acyloxy-, alkyl-, amino-, acylamino-, or halide-containing mescaline derivative compound and a glycosyl compound are contacted to react in a chemical reaction resulting in the formation of a glycosylated mescaline derivative compound.
  • the isopropylamine analogue of a glycosylated mescaline derivative can be formed in a reaction between a glycosyl compound and an isopropylamine analogue of a hydroxy-containing mescaline derivative, wherein the hydroxy group of the hydroxy-containing mescaline derivative reacts with the glycosyl compound to form a glycosidic bond.
  • the example reaction depicted in FIG.12 shows a reaction between a glucose and chemical compound (II) which is an isopropylamine analogue of a 4-hydroxy-mescaline derivative, wherein X 1 , X 3 , and X 5 are substituent groups, and wherein X 2 and X 4 are hydrogen atoms, wherein one of X 1 , X 3 , and X 5 one group, namely X 2 , is a hydroxy group, and wherein X 1 , X 3 are a methoxy group.
  • II glucose and chemical compound
  • one, two or three of X 1 , X 2 , X 3 , X 4 , and X 5 in compound (II) can be hydroxy groups.
  • one, two or three of X 2 , X 3 and X 4 in compound (II) can be a hydroxy group, wherein when (i) one of X 2 , X 3 , and X 4 , is an hydroxy group, the other two of X 2 , X 3 and X 4 are independently selected from a glycosyl group, an O-alkyl group, an O-acyl group, and each of X 1 and X 5 are a hydrogen atom, (ii) when two of X 2 , X 3 , and X 4 , are an hydroxy group, the other one of X 2 , X 3 and X 4 are selected from a glycosyl group an O-alkyl group, an
  • one, two or three of X 1 , X 3 and X 4 in compound (II) can be a hydroxy group, wherein when (i) one of X 1 , X 3 , and X 4 , is an hydroxy group, the other two of X 1 , X 3 and X 4 are independently selected from a glycosyl group, an O-alkyl group, an O-acyl group, and each of X 2 and X 5 are a hydrogen atom, (ii) when two of X 1 , X 3 , and X 4 , are an hydroxy group, the other one of X 1 , X 3 and X 4 is selected from a glycosyl group an O-alkyl group, an O-acyl group, and each of X 2 , and X 5 are a hydrogen atom, and (iii) when three of X 1 , X 3 , and X 4 , are an hydroxy group, each of X
  • one, two or three of X 1 , X 2 and X 3 in compound (II) can be a hydroxy group, wherein when (i) one of X 1 , X 2 , and X 3 , is an hydroxy group, the other two of X 1 , X 2 and X 3 are independently selected from a glycosyl group, an O-alkyl group, an O-acyl group, and each of X 4 and X 5 are a hydrogen atom, (ii) when two of X 1 , X 2 , and X 3 , are an hydroxy group, the other one of X 1 , X 2 and X 3 is selected from a glycosyl group an O-alkyl group, an O-acyl group, and each of X 4 , and X 5 are a hydrogen atom, and (iii) when three of X 1 , X 2 , and X 3 , are an hydroxy group, each of X
  • one, two or three of X 1 , X 3 and X 5 in compound (II) can be a hydroxy group, wherein when (i) one of X 1 , X 3 , and X 5 , is an hydroxy group, the other two of X 1 , X 3 and X 5 are independently selected from a glycosyl group, an O-alkyl group, an O-acyl group, and each of X 1 and X 5 are a hydrogen atom, (ii) when two of X 1 , X 3 , and X 5 , are an hydroxy group, the other one of X 1 , X 3 and X 5 is selected from a glycosyl group an O-alkyl group, an O-acyl group, and each of X 2 , and X 4 are a hydrogen atom, and (iii) when three of X 1 , X 3 , and X 5 , are an hydroxy group, each of X
  • one, two or three of X 1 , X 2 and X 4 in compound (II) can be a hydroxy group, wherein when (i) one of X 1 , X 2 , and X 4 , is an hydroxy group, the other two of X 1 , X 2 and X 4 are independently selected from a glycosyl group, an O-alkyl group, an O-acyl group, and each of X 3 and X 5 are a hydrogen atom, (ii) when two of X 1 , X 2 , and X 4 , are an hydroxy group, the other one of X 1 , X 2 and X 4 is selected from a glycosyl group an O-alkyl group, an O-acyl group, and each of X 3 , and X 5 are a hydrogen atom, and (iii) when three of X 1 , X 2 , and X 4 , are an hydroxy group, each of X
  • any two of the R4, R5, R6 groups can be joined together, R 1 and R 2 are independently or simultaneously a hydrogen atom, an alkyl group, or an acyl group, or R 1 and R 2 are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring.
  • R 1 , R 2 and R 3 are independently or simultaneously a hydrogen atom, an alkyl group, or an acyl group, or any two of R 1 , R 2 and R 3 are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • X 1 can be a hydroxy group.
  • X 2 and X 5 can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • X 2 can be a hydroxy group.
  • X 1 and X 3 can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • X 5 can be a hydroxy group. Furthermore, X 1 and X 3 can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group. [00293] Referring next to FIG.10D, and the chemical compound having the chemical formula (II), in one embodiment, X 1 and X 3 can each be a hydroxy group. Furthermore, X 5 can be selected from a hydroxy group, an O-alkyl group, or an O- acyl group.
  • X 1 and X 5 can each be a hydroxy group.
  • X 3 can be selected from a hydroxy group, an O-alkyl group, or an O- acyl group.
  • X 3 and X 5 can each be a hydroxy group.
  • X 1 can be a hydroxy group, an O-alkyl group, or an O-acyl group.
  • X 1 , X 3 and X 5 can each be a hydroxy group.
  • X 1 , X 3 and X 5 bonded to carbon atoms C 2 , C 4 and C 6 , respectively.
  • X 2 and X 4 are hydrogen atoms.
  • the compounds shown in FIGS.10A – 10G can be understood to correspond with the compound shown in FIG.3G.
  • FIGS.10A – 10G may be used to make the glycosyl mescaline derivatives shown in FIGS. 4A – 4G, respectively. It is to be clearly understood, that, in this respect, FIGS.10A – 10G represent example embodiments.
  • mescaline derivative compounds shown in FIGS.3A – 3F, and 3H – 3I may be selected, wherein any one, any two, or three of X 1 , X 2 , X 3 , X 4 , and X 5 can be a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein X 1 , X 2 , X 3 , X 4 , and X 5 which are not a glycosyl group or a hydrogen atom, can be independently selected from a hydroxy group, an O-alkyl group, or an O-acyl group.
  • isopropylamine analogues of hydroxy-containing mescaline derivatives may all be used to make isopropylamine analogues of glycosyl mescaline derivatives.
  • groups other than hydroxy groups may be used to facilitate a reaction between a glycosyl group and a mescaline derivative. These groups include, for example, alkoxy groups, alkyl groups, acylamido groups or halides, all of which may be included in mescaline derivatives in a manner similar to the hereinbefore described hydroxy-mescaline derivatives.
  • FIGS.11A and 11B Further example reactions to make isopropylamine analogues of glycosylated mescaline derivatives are depicted in FIGS.11A and 11B.
  • FIG.11A depicts example reactions for synthesizing isopropylamine analogues of glycosylated mescaline derivatives wherein the glycosyl groups are O-linked.
  • FIG. 11B depicts example reactions for synthesizing isopropylamine analogues of glycosylated mescaline derivatives wherein the glycosyl groups are C-linked.
  • FIG.11A depicts example reactions for synthesizing isopropylamine analogues of glycosylated mescaline derivatives wherein the glycosyl groups are O-linked.
  • FIG. 11B depicts example reactions for synthesizing isopropylamine analogues of glycosylated mescaline derivatives wherein the glycosyl groups are C-linked.
  • 11C depicts an example multistep synthesis of the isopropylamine analogues of C-glycosylated mescaline derivatives (11C-8), from 4-hydroxy-2,5-dimethoxybenzaldehyde (11C-1) using Henry reaction with nitroethane. This synthesis affords a racemic mixture of the final product (11C-8).
  • FIGS.11D – 11F illustrate an example of a multistep synthesis of both (R)- and (S)-isopropylamine analogues of 1,3- dimethoxy-2-O-glycosylated mescaline (11E-5), (11E-6), (11F-3) and (11F-4).
  • the synthesis employs a highly reactive 2-O-benzyl-1,3-dimethoxyphenyllithium intermediate (11D-3), which reacts with a N-Boc-protected 2-methylaziridine reagent ((11D-4) or (11D-6)), prepared in either (R)- or (S)- enantiomerically pure form (see: G. Bringmann, T. Gulder, B. Hertlein, Y. Hemberger, and F. Meyer, J. Am. Chem. Soc., 2010, 132, 1151–1158).
  • both the amine intermediates (11E-4) and (11F-2) can be sequentially N-alkylated to afford either the neutral amines (11E-5) and (11F-3), or the corresponding ammoniums (11E-6) and (11F-4) in each series. All of these compounds can be obtained in enantiomerically pure forms. It is noted that the stepwise N-alkylations can be performed using the alkyl halide or different alkyl halides to introduce diversity. [00302] Yet further example reactions to make glycosylated isopropylamine mescaline derivatives are depicted in FIGS.14A and 14B.
  • the present disclosure provides, a method of making a glycosylated mescaline derivative having the chemical formula (I): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O- alkyl group, an O-acyl group, or a hydroxy group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, and wherein W is -N(R 1 )(R 2 ) or -N + (R 1 )(R 2 )(R 3 ), wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, wherein (i) R 1 and R 2 are independently or simultaneously a hydrogen atom, wherein (i) R
  • the compound having formula (I) can be a compound having chemical formula (II) or (III): wherein O-Q is a glycosyloxy group, and wherein the method involves the performance of the chemical reactions selected from: (i) chemical reactions (e); (d) and (e); (c), (d) and (e); (b), (c), (d), and (e); or (a), (b), (c), (d), and (e), depicted in FIG.14A; or (ii) chemical reactions (j); (i) and (j); (h), (i) and (j); (g), (h), (i), and (j); or (f), (g), (h), (i), and (j), depicted in FIG.14B.
  • the compound having formula (II) can have the chemical formula (IV): and the chemical reaction can be selected from the chemical reactions: (e); (d) and (e); (c), (d) and (e); (b), (c), (d), and (e); or (a), (b), (c), (d), and (e), depicted in FIG.14A.
  • the compound having formula (III) can have the chemical formula (V): and the chemical reaction can be selected from: chemical reactions (j); (i) and (j); (h), (i) and (j); (g), (h), (i), and (j); or (f), (g), (h), (i), and (j) depicted in FIG.14B.
  • the present disclosure provides, a method of making a glycosylated mescaline derivative having the chemical formula (XI): wherein, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are a hydrogen atom, a glycosyl group, or an O-alkyl group, wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are a glycosyl group, wherein two of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are a hydrogen atom, and wherein one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 , and X 6 is an isopropyl amino group (-
  • the compound having formula (II) can be a compound having chemical formula (IV), [00309] In one embodiment, the compound having formula (III) can be a compound having chemical formula (V), [00310]
  • the reactants are reacted under reaction conditions which permit the reactants to chemically react with each other and form a product, i.e., the glycosylated mescaline derivatives of the present disclosure. Such reactions conditions may be selected, adjusted, and optimized as known by those of skill in the art.
  • the reaction may be catalyzed by initially preparing a glycosyl derivative compound to enhance the reactivity between the glycosyl compound and a hydroxy- containing mescaline derivative.
  • the anomeric carbon of the glycosyl compound may be complexed with a halogen, such as bromide and chloride, and furthermore the reaction may be performed in the presence of, for example, Ag 2 CO 3 or another heavy metal-based compound, which can act as an acid (HCl or HBr) scavenger.
  • glycosyl compound derivatives that may be used include acylate (such as acetate), imidate (such as trichloroacetimidate), thioalkyl or thioaryl of glycosyl compound derivatives.
  • acylate such as acetate
  • imidate such as trichloroacetimidate
  • thioalkyl or thioaryl of glycosyl compound derivatives e.g., acetate
  • the reactions may be conducted in any suitable reaction vessel (e.g., a tube, bottle).
  • suitable solvents that may be used are polar solvents such as, for example, dichloromethane, dichloroethane, toluene, and so-called participating solvents such as acetonitrile and diethyl ether.
  • Suitable temperatures may range from, for example, e.g., from about -78 oC to about 60 oC.
  • catalysts also known as promoters, may be included in the reaction such as iodonium dicollidine perchlorate (IDCP), any silver or mercury salts, trimethylsilyl trifluoromethanesulfonate (TMS-triflate, TMSOTf), or trifluoronmethanesulfonic acid (triflic acid, TfOH), N-iodosuccinimide, methyl triflate.
  • IDCP iodonium dicollidine perchlorate
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • TfOH trifluoronmethanesulfonic acid
  • reaction times may be varied.
  • the reaction conditions may be optimized, for example, by preparing several glycosyl compound preparations and hydroxy-containing mescaline derivative preparations and reacting these in different reaction vessels under different reaction conditions, for example, different temperatures, using different solvents etc., evaluating the obtained glycosylated mescaline derivative reaction product, adjusting reaction conditions, and selecting a desired reaction condition. Further general guidance regarding appropriate reaction conditions for performing glycosylation reactions may be found in Demchenko, A., handbook of chemical glycosylation: advances in stereoselectivity and therapeutic relevance, 2008, Wiley-VCH Verlag GmbH. [00312] In one example embodiment, the reaction may be catalyzed by a glucosyl transferase.
  • FIG. 13 shown therein is an example chemical reaction catalyzed by a UDP glycosyl transferase wherein the glucose moiety of UDP-glucose is transferred to an isopropylamine analogue of a 3- hydroxy-mescaline derivative in a chemical reaction which results in the formation of a glycosidic bond, and which is catalyzed by a UDP glycosyl transferase.
  • the isopropylamine analogue of a glycosylated mescaline derivative can be formed in a reaction between a UDP- glycosyl compound and an isopropylamine analogue of a hydroxy-containing mescaline derivative, wherein the hydroxy group reacts with the glycosyl group of the UDP-glycosyl compound to form a glycosidic bond, and wherein the reaction is catalyzed by the UDP-glycosyl transferase.
  • the reaction shown in FIG.13 involves the use of an isopropylamine analogue of a hydroxy-containing mescaline derivative. Furthermore, the reaction shown in FIG.13 can be carried out in vitro.
  • reaction constituents i.e., an isopropylamine analogue of a hydroxy-containing mescaline derivative, a glycosyl compound, and a glycosyl transferase
  • Suitable in vitro reaction conditions are generally reaction conditions which are approximately physiological conditions.
  • in vitro physiological conditions can comprise, for example, 50-200 mM NaCl or KCl, pH 6.5-8.5, 20-45° C, or 30- 40° C.
  • aqueous conditions may be selected by the practitioner according to conventional methods.
  • buffered aqueous conditions may be applicable: 10-250 mM NaCl, 5-50 mM Tris HC 1 , pH 5-8, with optional addition of divalent cation(s) and/or metal chelators and/or non-ionic detergents and/or membrane fractions and/or anti-foam agents and/or scintillants. All reaction constituents may be mixed, for example by gentle stirring or shaking the reaction vessel. Reaction times may vary, but generally the glycosylated mescaline compound can be formed in less than about 30 minutes, for examples less than about 20 minutes, or less than about 5 minutes.
  • glycosylated mescaline derivatives may be formed biosynthetically.
  • the present disclosure further includes in one embodiment, a method of making a glycosylated mescaline derivative, the method comprising: (a) contacting a hydroxy-containing mescaline derivative compound with a host cell comprising a glycosyl transferase, wherein the hydroxy- containing mescaline derivative compound has the formula (XII): wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are a hydrogen atom, a glycosyl group, an O-alkyl group, an O-acyl group, or a hydroxy group wherein 1 to 3 of X 1 , X 2 , X 3 , X 4 , and X 5 , are a hydroxy group, alkoxy group, acyloxy group, alkyl group, amino group, acylamino group, or a halide, wherein two of X 1 , X 2 , X 3 , X 4 , and X
  • the host cell includes a glycosyl transferase.
  • Such cells can be obtained in at least two ways. First, in some embodiments, host cells may be selected in which a glycosyl transferase is naturally present. Second, in some embodiments, a host cell that not naturally produces a suitable glycosyl transferase may modulated to produce a glycosyl transferase.
  • a nucleic acid sequence encoding a glycosyl transferase may be introduced into a host cell, and upon cell growth the host cells can make the glycosyl transferase.
  • a nucleic acid sequence encoding a glycosyl transferase further includes one or more additional nucleic acid sequences, for example, a nucleic acid sequences controlling expression of the glycosyl transferase, and these one or more additional nucleic acid sequences together with the nucleic acid sequence encoding the glycosyl transferase can be said to form a chimeric nucleic acid sequence.
  • a host cell which upon cultivation expresses the chimeric nucleic acid can be selected and used in accordance with the present disclosure.
  • Suitable host cells in this respect include, for example, microbial cells, such as bacterial cells, yeast cells, for example, and algal cells or plant cells.
  • microbial cells such as bacterial cells, yeast cells, for example, and algal cells or plant cells.
  • algal cells or plant cells A variety of techniques and methodologies to manipulate host cells to introduce nucleic acid sequences in cells and attain expression exists and are well known to the skilled artisan. These methods include, for example, cation-based methods, for example, lithium ion or calcium ion-based methods, electroporation, biolistics, and glass beads- based methods.
  • the methodology to introduce nucleic acid material in the host cell may vary, and, furthermore, methodologies may be optimized for uptake of nucleic acid material by the host cell, for example, by comparing uptake of nucleic acid material using different conditions.
  • Detailed guidance can be found, for example, in Sambrook et al., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory Press, 2012, Fourth Ed. It is noted that the chimeric nucleic acid is a non-naturally occurring chimeric nucleic acid sequence and can be said to be heterologous to the host cell.
  • the glycosyl transferase can be selected a nucleic acid sequence selected from the nucleic acid sequences consisting of: (a) SEQ.ID NO: 1, SEQ.ID NO: 3, and SEQ.ID NO: 5; (b) a nucleic acid sequence that is substantially identical to any one of the nucleic acid sequences of (a); (c) a nucleic acid sequence that is substantially identical to any one of the nucleic acid sequences of (a) but for the degeneration of the genetic code; (d) a nucleic acid sequence that is complementary to any one of the nucleic acid sequences of (a); (e) a nucleic acid sequence encoding a polypeptide having any one of the amino acid sequences set forth in SEQ.ID NO: 2, SEQ.ID NO: 4, or SEQ.ID NO: 6; (f) a nucleic acid sequence that encodes a functional variant of any one of the amino acid sequences set forth in SEQ.ID NO: 2, SEQ
  • any of the nucleic acid sequences set forth in (a), (b), (c), (d), (e), (f) or (g) may be selected and introduced into a host cell.
  • One example host cell that conveniently may be used is Escherichia coli.
  • the preparation of the E. coli vectors may be accomplished using commonly known techniques such as restriction digestion, ligation, gel electrophoresis, DNA sequencing, the polymerase chain reaction (PCR) and other methodologies.
  • PCR polymerase chain reaction
  • a wide variety of cloning vectors is available to perform the necessary steps required to prepare a recombinant expression vector.
  • PCR polymerase chain reaction
  • coli are vectors such as pBR 3 22, the pUC series of vectors, the M13 mp series of vectors, pBluescript etc.
  • Suitable promoter sequences for use in E. coli include, for example, the T7 promoter, the T5 promoter, tryptophan (trp) promoter, lactose (lac) promoter, tryptophan/lactose (tac) promoter, lipoprotein (Ipp) promoter, and ⁇ phage PL promoter.
  • cloning vectors contain a marker, for example, an antibiotic resistance marker, such as ampicillin or kanamycin resistance marker, allowing selection of transformed cells.
  • Nucleic acid sequences may be introduced in these vectors, and the vectors may be introduced in E. coli by preparing competent cells, electroporation or using other well-known methodologies to a person of skill in the art.
  • E. coli may be grown in an appropriate medium, such as Luria-Broth medium and harvested.
  • Recombinant expression vectors may readily be recovered from cells upon harvesting and lysing of the cells.
  • Another example host cell that may be conveniently used is a yeast cell.
  • Example yeast host cells that can be used are yeast cells belonging to the genus Candida, Kluyveromyces, Saccharomyces, Schizosaccharomyces, Pichia, Hansenula, and Yarrowia.
  • the yeast cell can be a Saccharomyces cerevisiae cell, a Yarrowia lipolytica cell, or Pichia pastoris cell.
  • yeast host cells A number of vectors exist for the expression of recombinant proteins in yeast host cells.
  • Such vectors are known to the art and are, for example, described in Cregg et al., Mol Biotechnol. (2000) 16(1): 23-52.
  • Suitable promoter sequences for use in yeast host cells are also known and described, for example, in Mattanovich et al., Methods Mol. Biol., 2012, 824:329-58, and in Romanos et al., 1992, Yeast 8: 423- 488.
  • suitable promoters for use in yeast host cells include promoters of glycolytic enzymes, like triosephosphate isomerase (TPI), phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH or GAP) and variants thereof, lactase (LAC) and galactosidase (GAL), P.
  • TPI triosephosphate isomerase
  • PGK phosphoglycerate kinase
  • GAP glyceraldehyde-3-phosphate dehydrogenase
  • LAC lactase
  • GAL galactosidase
  • PPGI glucose-6- phosphate isomerase promoter
  • PPGK 3-phosphoglycerate kinase promoter
  • GAP glycerol aldehyde phosphate dehydrogenase promoter
  • PTEF translation elongation factor promoter
  • ENO-1 S. cerevisiae enolase
  • GAL1 S. cerevisiae galactokinase
  • ADH1, ADH2/GAP S. cerevisiae triose phosphate isomerase
  • TPI glucose-6- phosphate isomerase
  • yeast host cells can be used in yeast, as well as marker genes providing genetic functions for essential nutrients, for example, leucine (LEU2), tryptophan (TRP1 and TRP2), uracil (URA3, URA5, URA6), histidine (HIS3), and the like.
  • LEU2 leucine
  • TRP1 and TRP2 tryptophan
  • URA6 uracil
  • HIS3 histidine
  • a host cell comprising a chimeric nucleic acid comprising (i) a nucleic acid sequence controlling expression in a host cell and (ii) a nucleic acid sequence encoding a glycosyl transferase, can be prepared in accordance with the present disclosure.
  • host cells are grown to multiply and to express a chimeric nucleic acid. Expression of the chimeric nucleic acid results in the biosynthetic production in the host cell of a glycosyl transferase.
  • Growth media and growth conditions can vary depending on the host cell that is selected, as will be readily appreciated to those of ordinary skill in the art. Growth media typically contain a carbon source, one or several nitrogen sources, essential salts including salts of potassium, sodium, magnesium, phosphate and sulphate, trace metals, water soluble vitamins, and process aids including but not limited to antifoam agents, protease inhibitors, stabilizers, ligands and inducers.
  • Example carbon sources are e.g., mono- or disaccharides.
  • Example nitrogen sources are, e.g., ammonia, urea, amino acids, yeast extract, corn steep liquor and fully or partially hydrolyzed proteins.
  • Example trace metals are e.g., Fe, Zn, Mn, Cu, Mo and H 3 BO3.
  • Example water soluble vitamins are e.g., biotin, pantothenate, niacin, thiamine, p- aminobenzoic acid, choline, pyridoxine, folic acid, riboflavin, and ascorbic acid.
  • specific example media include liquid culture media for the growth of yeast cells and bacterial cells including, Luria-Bertani (LB) broth for bacterial cell cultivation, and yeast extract peptone dextrose (YEPD or YPD), for yeast cell cultivation.
  • LB Luria-Bertani
  • YEPD yeast extract peptone dextrose
  • the hydroxy-containing mescaline can be exogenously supplied, for example, by including a hydroxy-containing mescaline derivative in the growth medium of the host cells and growing the host cells in a medium including the hydroxy-containing mescaline derivative.
  • the glycosylated mescaline derivative compounds may be extracted from the host cell suspension and separated from other constituents within the host cell suspension, such as media constituents and cellular debris.
  • glycosylated mescaline derivative compounds may be obtained in a more or less pure form, for example, a preparation of glycosylated mescaline derivative compounds of at least about 60% (w/v), about 70% (w/v), about 80% (w/v), about 90% (w/v), about 95% (w/v) or about 99% (w/v) purity may be obtained.
  • glycosylated mescaline derivatives in more or less pure form may be prepared.
  • novel glycosylated mescaline derivatives are disclosed herein, as well as methods of making glycosylated mescaline derivatives.
  • the glycosylated mescaline compounds may be formulated for use as a pharmaceutical drug or recreational drug.
  • SEQ.ID NO: 1 sets forth a Nicotiana benthamiana nucleic acid sequence encoding a glycosyl transferase.
  • SEQ.ID NO: 2 sets forth a deduced amino acid sequence of a Nicotiana benthamiana glycosyl transferase polypeptide.
  • SEQ.ID NO: 3 sets forth a Nicotiana benthamiana nucleic acid sequence encoding a glycosyl transferase.
  • SEQ.ID NO: 4 sets forth a deduced amino acid sequence of a Nicotiana benthamiana glycosyl transferase polypeptide.
  • SEQ.ID NO: 5 sets forth a Nicotiana benthamiana nucleic acid sequence encoding a glycosyl transferase.
  • SEQ.ID NO: 6 sets forth a deduced amino acid sequence of a Nicotiana benthamiana glycosyl transferase polypeptide.
  • SEQUENCE LISTING EXAMPLES Example 1 – Preparation and pharmacological evaluation of a first glycosylated isopropylamine mescaline derivative.
  • compound 1 (1.2 g, 6.46 mmol), compound 2 (3.19 g, 7.75 mmol) and cesium carbonate (2.55 g, 7.75 mmol) were added into acetonitrile (24 mL) in a round bottom flask, and the resulting mixture was stirred at room temperature overnight.
  • PrestoBlue assays were first performed. The PrestoBlue assay measures cell viable activity based on the metabolic reduction of the redox indicator resazurin and is a preferred method for routine cell viability assays (Terrasso et al., 2017, J Pharmacol. Toxicol. Methods 83: 72).
  • Results of these assays were conducted using both control ligands (e.g., 2C-B (4-bromo-2,5-dimethoxyphenethylamine), MDMA, mescaline, etc.) and novel derivative, in part as a pre-screen for any remarkable toxic effects on cell cultures up to concentrations of 1 mM.
  • control ligands e.g., 2C-B (4-bromo-2,5-dimethoxyphenethylamine), MDMA, mescaline, etc.
  • novel derivative in part as a pre-screen for any remarkable toxic effects on cell cultures up to concentrations of 1 mM.
  • a known cellular toxin (Triton X-100, Pyrgiotakis G. et al., 2009, Ann. Biomed. Eng. 37: 1464-1473) was included as a general marker of toxicity.
  • HepG2 Drug-induced changes in cell health within simple in vitro systems such as the HepG2 cell line are commonly adopted as first-line screening approaches in the pharmaceutical industry (Weaver et al., 2017, Expert Opin. Drug Metab. Toxicol.13: 767).
  • HepG2 is a human hepatoma that is most commonly used in drug metabolism and hepatotoxicity studies (Donato et al., 2015, Methods Mol Biol 1250: 77).
  • HepG2 cells were cultured using standard procedures using the manufacture’s protocols (ATCC, HB-8065). Briefly, cells were cultured in Eagle’s minimum essential medium supplemented with 10% fetal bovine serum and grown at 37 °C in the presence of 5% CO 2 .
  • FIGS.17A(i) and 17A(ii) show results for phenylalkylamine compounds 2C-B (4-bromo-2,5- dimethoxyphenethylamine) (Panel A), MDMA (Panel B), mescaline (Panel C), and the toxic control compound Triton X100 (Panel D). Data acquired for the derivative having chemical formula (V) is displayed as “(V)” on the x-axis in Panel E. Radioligand 5-HT 1A receptor binding assays.
  • SPA beads RPNQ0011
  • radiolabeled 8-hydroxy-DPAT [propyl-2,3- ring-1,2,3- 3 H]
  • isoplate-96 microplate 6005040
  • Radioactive binding assays were carried out using the Scintillation Proximity Assay (SPA).
  • binding buffer 50 mM Tris-HCl pH 7.4, 10 mM MgSO 4 , 0.5 mM EDTA, 3.7% glycerol, 1 mM ascorbic acid, 10 ⁇ M pargyline HCl.
  • the beads and membrane were aliquoted in an isoplate-96 microplate with increasing amounts of 8-hydroxy-DPAT [propyl-2,3- ring-1,2,3- 3 H] (0.1525 nM to 5 nM) and incubated for two hours at room temperature in the dark with shaking. After incubation, the samples were read on a MicroBeta 2 Microplate Counter. Non-specific binding was carried out in the presence of 100 ⁇ M of metergoline (M3668-500MG, Sigma). Equilibrium binding constant for 8-hydroxy-DPAT (K D ) was determined from saturation binding curve using one-site saturation binding analysis from GraphPad PRISM software (Version 9.2.0).
  • test compounds were dissolved to 100 mM in DMSO, and dilutions were carried out in assay buffer.
  • Competition binding assays were performed using 0.5 nM hot 8-hydroxy-DPAT and different concentrations of DMSO (up to 1%), tryptophan (3 nM to 1 mM), or unlabelled test compounds (3 nM to 1 mM) similar to the saturation binding assay. Ki values were calculated from the competition displacement data using the competitive binding analysis from GraphPad PRISM software.
  • FIGS. 17B, 17C and 17D show the competition binding curves for 2C-B, MDMA and mescaline, respectively, as positive controls (binding).
  • FIGS.17E and 17F show the competition binding curves for escaline and proscaline, respectively, for comparative purposes.
  • FIGS.17G and 17H show the competition binding curves for DMSO and tryptophan, respectively, as negative controls (no binding).
  • the competition binding curve for compound with formula (V), designated “(V)” in FIG. 17I reveals binding at higher ligand concentrations. Radioligand 5-HT2C receptor binding assays.
  • Non-specific binding was carried out in the presence of 10 ⁇ M of ( ⁇ )DOI, and K D for [ 125 I]( ⁇ )DOI was determined from the saturation binding curve.
  • 2C-B (4-bromo-2,5- dimethoxyphenethylamine) and 5-MeO-MiPT (N-[2-(5-methoxy-1H-indol-3- yl)ethyl]-N-methylpropan-2-amine) were used as positive controls since they are known binders at this receptor (2C-B, Rickli et al., Neuropharm 99: 546-553, 2015; 5-MeO-MiPT, Rickli et al., Eur Neuropsychopharm 26: 1327-1337, 2016).
  • CHO-K1/Galpha15 (GenScript, M00257) (-5-HT 2A ) and CHO-K1/5- HT 2A (GenScript, M00250) (+5-HT 2A ) cells lines were used in calcium release assays. Briefly, CHO-K1/Galpha15 is a control cell line that constitutively expresses Galpha15 which is a promiscuous Gq protein.
  • transfected receptor(s) it is engineered as a host cell, allowing transfected receptor(s) to signal through the Gq signal transduction pathway and mobilize intracellular calcium from the endoplasmic reticulum (ER).
  • ER endoplasmic reticulum
  • These control cells lack any transgene encoding 5-HT 2A receptors, thus preventing calcium mobilization in response to 5-HT 2A activation.
  • CHO-K1/5- HT 2A cells stably express 5-HT 2A receptor in the CHO-K1 host background. This design enables Gq-11 expressed in CHO-K1 cells to mobilize intracellular calcium changes when 5-HT 2A receptors are activated by ligands.
  • Cell lines were maintained in Ham’s F12 media plus 10% FBS in the presence of 100 ug/ml hygromycin for CHO-K1/Ga15 or 400 ug/ml G418 for CHO-K1/5-HT 2A unless indicated otherwise for specific assays.
  • Cell maintenance was carried out as recommended by the cell supplier. Briefly, vials with cells were removed from the liquid nitrogen and thawed quickly in 37 °C water bath. Just before cells were completely thawed, vial exteriors were decontaminated with 70% ethanol spray. Cell suspension was then retrieved from the vial and added to warm (37 °C), ‘complete’ (non-dropout) growth media, and centrifuged at 1,000 rpm for 5 minutes.
  • CHO-K1 cells stably expressing 5-HT 2A (Genscript # M00250) (+5-HT 2A ) or lacking 5-HT 2A (Genscript, M00257) (-5-HT 2A ) were seeded on black walled clear bottom 96-well plates (Thermo Scientific #NUNC 1 65305), allowing 70,000 cells/well in 100 ul media (HAM’s F12, GIBCO #11765-047) with 1% FBS (Thermo Scientific #12483020). Cultures were maintained in a humidified incubator at 37 °C and 5% CO 2 . Fluo-8 dye was loaded into the cultures for 30 min at 37 °C, followed by 30 min additional incubation at room temperature.
  • Serotonin and DMT are known agonists with binding activity at 5-HT 2A (Ray, PLoS ONE 5: e9019, 2010) and were thus used as positive controls to establish assay functionality.
  • the Example compound (V) was then evaluated. Results for positive controls are shown in FIG.17J (serotonin) and FIG.17K (DMT), for which EC 50 values of 0.07865 ⁇ M and 6.325 ⁇ M were obtained, respectively, which are indicative of 5-HT 2A receptor stimulation. Conversely, a near-zero % stimulation and an EC 50 value >1,000 ⁇ M was observed for compound (V), revealing a lack of significant 5-HT2A receptor stimulation for this molecule (V) (FIG.17L).
  • Example 2 Preparation and pharmacological evaluation of a second glycosylated isopropylamine mescaline derivative.
  • compound 1 (2.04 g, 11.0 mmol), compound 2 (5.42 g, 13.2 mmol) and cesium carbonate (4.34 g, 13.2 mmol) were added to acetonitrile (40 mL) in a round bottom flask. The resulting mixture was stirred overnight at room temperature. Water and EtOAc were added to the reaction mixture and the aqueous phase was extracted with EtOAc, and the organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • compound MM742 corresponds with compound (IV) set forth herein: Assessment of cell viability upon treatment of a psilocin derivative.
  • Cell viability was assessed as described for Example 1, except the compound with formula (IV) was evaluated in place of the compound with formula (V).
  • Data acquired for the derivative having chemical formula (IV) is displayed as “(IV)” on the x-axes in FIG.18A.
  • Radioligand 5-HT 1A receptor binding assays [00364]
  • Activity at 5-HT 1A receptor was assessed as described for Example 1, except the compound with formula (IV) was evaluated in place of the compound with formula (V).

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Abstract

L'invention divulgue de nouveaux composés dérivés de mescaline, notamment des dérivés d'isopropylamine glycosylés de mesclaline, et des formulations pharmaceutiques et de médicaments de loisir les contenant. Les composés peuvent être produits par réaction d'un dérivé d'isopropylamine d'un dérivé de mescaline hydroxylé avec un composé glycosyle.
PCT/CA2022/051793 2021-12-08 2022-12-08 Dérivés de mescaline d'isopropylamine glycosylés et leurs méthodes d'utilisation Ceased WO2023102659A1 (fr)

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* Cited by examiner, † Cited by third party
Title
CASSELS BRUCE K., SÁEZ-BRIONES PATRICIO: "Dark Classics in Chemical Neuroscience: Mescaline", ACS CHEMICAL NEUROSCIENCE, AMERICAN CHEMICAL SOCIETY, US, vol. 9, no. 10, 17 October 2018 (2018-10-17), US , pages 2448 - 2458, XP093072662, ISSN: 1948-7193, DOI: 10.1021/acschemneuro.8b00215 *

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