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WO2024211360A2 - Agents d'inversion spécifiques pour traiter la toxicité aiguë et chronique de fentanyls - Google Patents

Agents d'inversion spécifiques pour traiter la toxicité aiguë et chronique de fentanyls Download PDF

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Publication number
WO2024211360A2
WO2024211360A2 PCT/US2024/022762 US2024022762W WO2024211360A2 WO 2024211360 A2 WO2024211360 A2 WO 2024211360A2 US 2024022762 W US2024022762 W US 2024022762W WO 2024211360 A2 WO2024211360 A2 WO 2024211360A2
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nmr
mhz
fentanyl
dmso
compound
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WO2024211360A3 (fr
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Yan Zhang
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Virginia Commonwealth University
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Virginia Commonwealth University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention provides agents having a structural skeleton similar to that of fentanyl and/or phenylfentanil and which recognize and antagonize the mu opioid receptor (MOR) selectively, thereby competing with fentanyl at the MOR without activating the MOR.
  • MOR mu opioid receptor
  • NLX has a relatively low potency to reverse the respiratory depression caused by fentanyls, which has been perceived as the major cause for overdose deaths.
  • Nalmefene has a half-life of 11 h, much longer than naloxone, but it is not yet clear whether nalmefene will prevent renarcotization.
  • nalmefene has high affinity towards the kappa opioid receptor, which may lead to some off-target effects.
  • fentanyl showed binding affinity in the single digit micromolar range at the ⁇ 1A and ⁇ 1B adrenoceptor subtypes as well as the dopamine D4.4 and D1 receptor subtypes.
  • morphine and other epoxymorphinan derivatives including naloxone, naltrexone, and nalmefene, do not carry such an affinity to those receptors.
  • naloxone may be ineffective against the centrally mediated noradrenergic and cholinergic effects of fentanyls.
  • MOR mu opioid receptor
  • the compounds bind specifically or selectively.
  • the compounds specifically and effectively reverse the acute and chronic toxicity of fentanyl and its analogs.
  • the antagonists were developed by modifying the structural skeleton of fentanyl and/or phenylfentanil. The antagonists compete with fentanyls at the MOR binding site.
  • the compound is .
  • R is substituted C1-C16 alkyl, unsubstituted C1-12 alkyl, aryl, heteroaryl or substituted aryl.
  • R1 is substituted C1-C16 alkyl, unsubstituted C1-16 alkyl, aryl, heteroaryl or substituted aryl.
  • the substituted C1-C16 alkyl is substituted with N, O or S.
  • a method of toxicity or overdose in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one of the compounds disclosed herein.
  • BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Antinociceptive effects of VZFN compounds using the warm water tail immersion study in mice (n 6) at 56 ⁇ 0.1 °C. All compounds were administered subcutaneously at a single dose of 10 mg/kg. Saline was adopted as the negative control while morphine and fentanyl were adopted as positive controls. Tail withdrawal latency was monitored 20 min post-injection in this agonism study. Data is represented as mean values ⁇ SD. Figure 2.
  • Error bars represent the standard error of minute volume (MVb) mean values within individual 5 min bins. Open symbols indicate significant differences compared to the MVb or saline (SAL) treated controls at individual timepoints (P ⁇ 0.05) via one-way ANOVA.
  • Figure 7A-C Dose dependent effects of (A)VZFN093, (B) VZFN094 and (C) VZFN202 on fentanyl induced respiratory depression in mice. Error bars represent the standard error of normalized mean values within individual 5 min bins. Open symbols indicate significant differences compared to the fentanyl (0.3 FEN + SAL)-treated controls at individual timepoints (P ⁇ 0.05) via one-way ANOVA.
  • Figure 8
  • Figure 9 Design strategy of target phenylfentanil analogs.
  • Figure 10A and B Calcium mobilization assay of Compound 3 as an agonist (A) or as an antagonist (B) in the presence of DAMGO or fentanyl. Naltrexone (NTX) was used as the control.
  • NTX Naltrexone
  • A Antinociceptive effects of compounds 3-19 (10 mg/kg).
  • ⁇ 1A-AR active and ⁇ 1A-AR inactive receptors are shown in grey and cyan cartoon representations. Interacting residues in the orthosteric binding pocket are shown as orange sticks and in the secondary pocket are shown as blue sticks. Fentanyl and Compound 3 are shown as magenta and green sticks, respectively. Figure 16. Highest scored docking pose of fentanyl at the (A) active ⁇ 1B- AR (gray) and (B) inactive ⁇ 1B- AR (cyan) and Compound 3 at the (C) active ⁇ 1B- AR (gray) and (D) inactive ⁇ 1B- AR (cyan). Interacting residues occupying the orthosteric site are shown as orange sticks and those parts of the secondary pocket are shown as salmon sticks.
  • Fentanyl and Compound 3 are shown as magenta and green sticks, respectively.
  • DETAILED DESCRIPTION DEFINITIONS Fentanyl (also known as fentanil) is a potent synthetic narcotic analgesic with a rapid onset and short duration of action. It is a strong agonist at the ⁇ -opioid receptors. It is manufactured under the trade names of SUBLIMAZE®, ACTIQ®, DUROGESIC®, DURAGESIC®, FENTORA®, ONSOLIS INSTANYL®, ABSTRAL® and others. Congeners refers to chemical substances related to each other by origin, structure, or function.
  • the congeners discussed herein are structural and/or chemical analogs and/or derivatives of fentanyl.
  • Structural and/or chemical analogs (analogues) as used herein are compounds in which one or more individual atoms have been replaced, either with a different atom, or with a different functional group.
  • a derivative as used herein a compound that is derived from a similar compound by at least one chemical reaction.
  • a C1-C16 carbon group is, for example, a C1-C16 carbon group that is saturated (e.g., C1-C16 alkyl) or unsaturated (having one or more double or triple bonds between C atoms), substituted (e.g., C1-C16 heteroalkyl) or unsubstituted, or cyclic (which can also be substituted or non-substituted and saturated or unsaturated) or non-cyclic (straight- chain or branched).
  • C1-C16 alkyl as used herein means a straight or branched (non-cyclic) hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or 16 carbon atoms.
  • the C1-C16 alkyl is unsubstituted, examples of which include but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2- methylbutyl, 3-methylbutyl, 1,2-dinnethylpropyl, 1 ,1-dimethylpropyl, 2,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1- dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1 ,2-trimethylpropyl
  • the C1-C62-alkyl group is cyclic and can include or consist of a 3C- 16C mono- or polycyclic cycloalkyl group containing only C atoms.
  • 3C-C62-cycloalkyl encompasses mono-, bi- or tricyclic hydrocarbyl groups having 3 to 16 carbon atoms.
  • these groups are (C5-C16)-cycloalkyl.
  • the 3C-C16-cycloalkyl groups have preferably 3 to 8, more preferably 5 or 6, atoms in each ring.
  • the 3C-C16-cycloalkyl groups have preferably 3 to 8, more preferably 5 or 6, ring atoms.
  • Suitable C3-C16 cycloalkyl groups include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, undecanyl, cyclododecyl, cyclopentadecyl, norbornyl, and adamantly, and including macrocycles, i.e., molecules and ions containing a ring of twelve or more atoms.
  • Classical examples include crown ethers, calixarenes, porphyrins, and cyclodextrins.
  • a heteroatom or heteroatomic group
  • Suitable C3-C16-heterocycloalkyl groups include but are not limited to tetrahydrothiophenyl, tetrahydrofuryl, tetrahydropyranyl and dioxanyl.
  • the expression C3-C16-cycloalkyl or C3-C16-heterocycloalkyl encompasses nonaromatic, saturated or partly unsaturated cycloaliphatic groups having 3 to 16 carbon atoms.
  • aryl means an aromatic group having up to 14 carbon atoms.
  • Aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.
  • Substituted phenyl and “substituted aryl” denote a phenyl group and aryl group, respectively, substituted with one, two, three, four or five (e.g.
  • heteroaryl refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems.
  • Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.
  • heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
  • heteroaryl includes N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent.
  • aryl when used without the “substituted” modifier also refers to a monovalent group, having a aromatic carbon atom as the point of attachment, said carbon atom forming part of a six-membered aromatic ring structure wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen.
  • Non-limiting examples of substituted aryl groups include the groups: -C6H4F, -C6H4Cl, -C6H4Br, -C6H4I, -C6H4OH, -C6H4OCH3, - C 6 H 4 OCH 2 CH 3 , -C 6 H 4 OC(O)CH 3 , -C 6 H 4 NH 2 , -C 6 H 4 NHCH 3 , -C 6 H 4 N(CH 3 ) 2 , -C6H 4 CH 2 OH, -C6H4CH2OC(O)CH3, -C6H4CH2NH2, -C6H4CF3, -C6H4CN, -C6H4CHO, -C6H4CHO, -C6H4CHO, - C 6 H 4 C(O)CH 3 , -C 6 H 4 C(O)C 6 H5, -C 6 H 4 4CO 2 H, -C 6 H 4 CO 2
  • a “biologically active” or “physiologically active” compound is one that has an effect on living matter, usually within the body of a mammal, particularly one which is an antagonist of fentanyls at the MOR binding site.
  • An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.
  • a “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs.
  • Enantiomers are stereoisomers of a given compound that are mirror images of each other, like left and right hands.
  • Diastereomers are stereoisomers of a given compound that are not enantiomers.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • Spacer or linker refers to a short chain of atoms (e.g., from about 1-10 atoms). Spacers may contain C atoms (e.g. a C1-C6 alkyl chain) or may be heteroatomic.
  • heteroatomic linker refers to a linker group comprising carbon and one or more heteroatoms.
  • Specificity describes the extent to a drug produces only the desired therapeutic effect without causing any other physiological changes.
  • a drug with high specificity exhibits a strong drug–receptor interaction, ensuring targeted action and minimal side effects.
  • Selectivity describes a drug's ability to affect a particular cell population in preference to others.
  • the compound is , , 5 A depiction of a generic synthesis scheme of compounds of these aspects is shown below: In further aspects, the compound .
  • PHARMACEUTICAL COMPOSITIONS The compounds described herein are generally delivered (administered) as a pharmaceutical composition. Such pharmaceutical compositions generally comprise at least one of the disclosed compounds, i.e., one or more than one (a plurality) of different compounds (e.g., 2 or more such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) may be included in a single formulation. Accordingly, the present invention encompasses such formulations/compositions.
  • compositions generally include one or more substantially purified compounds as described herein, and a pharmacologically suitable (physiologically compatible, biologically compatible) carrier, which may be aqueous or oil-based.
  • a pharmacologically suitable (physiologically compatible, biologically compatible) carrier which may be aqueous or oil-based.
  • such compositions are prepared as liquid solutions or suspensions, or as solid forms such as tablets, pills, powders and the like.
  • Solid forms suitable for solution in, or suspension in, liquids prior to administration are also contemplated (e.g., lyophilized forms of the compounds), as are emulsified preparations.
  • the liquid formulations are aqueous or oil-based suspensions or solutions.
  • the active ingredients are mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredients, e.g. pharmaceutically acceptable salts.
  • Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol and the like, or combinations thereof.
  • the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, preservatives, and the like. If it is desired to administer an oral form of the composition, various thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders and the like are added.
  • the composition of the present invention may contain any such additional ingredients so as to provide the composition in a form suitable for administration.
  • the final amount of compound in the formulations varies, but is generally from about 1-99%.
  • compositions for use in the present invention are found, for example in Remington's Pharmaceutical Sciences, 22nd ed. (2012; eds. Allen, Adejarem Desselle and Felton).
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as Tween® 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugar
  • “Pharmaceutically acceptable salts” of the compounds refers to the relatively non- toxic, inorganic and organic acid addition salts and base addition salts of compounds of the present disclosure. In some aspects, these salts are prepared in situ during the final isolation and purification of the compounds.
  • acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus
  • Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,
  • Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed.
  • Base addition salts include pharmaceutically acceptable metal and amine salts.
  • Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts.
  • Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like.
  • Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use.
  • ammonia ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine,
  • the salt is an HCl (hydrochloride) salt.
  • the pharmaceutical preparation is administered in vivo by any suitable route including but not limited to: inoculation or injection (e.g. intravenous, intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, and the like); or by absorption through epithelial or mucocutaneous linings (e.g., nasal, oral, gastrointestinal mucosa, and the like).
  • suitable means include but are not limited to: inhalation (e.g. intranasally as a mist or spray), orally (e.g. as a pill, capsule, liquid, etc.), etc.
  • the mode of administration is topical or oral or by injection.
  • compositions may be administered in conjunction with other treatment modalities such as pain medications, buprenorphine (to treat respiratory depression), oxygen, adenaline, and the like.
  • administration is generally by inhalation or IM injection.
  • METHODS Provided herein are methods of reversing the acute and chronic toxicity of fentanyl or analogs thereof.
  • the reversal involves treating an overdose of fentanyl or analog (analogue) thereof and/or fentanyl poisoning/toxicity (or poisoning with a fentanyl analog) in a subject in need thereof.
  • Such methods generally comprise administering to the subject a therapeutically effective amount of at least one novel compound disclosed herein.
  • a therapeutically effective amount is typically an amount sufficient to eliminate or lessen at least one symptom of the toxicity or overdose.
  • the methods comprise first (prior to the step of administering) a step of identifying a subject suffering from or suspected of suffering from toxicity and/or an overdose of or poisoning with fentanyl or a fentanyl analog.
  • Such subjects generally exhibit one or more symptoms of overdose/toxicity such as: stupor, changes in pupillary size, cold and clammy skin, cyanosis, coma, and respiratory depression (which may lead to respiratory failure and death).
  • the presence of triad of symptoms such as coma, pinpoint pupils, and respiratory depression are strongly suggestive of opioid poisoning.
  • the methods of the present disclosure encompass administering a therapeutically effective amount of at least one compound described herein to eliminate or lessen at least one of such symptoms.
  • such cases are caused by the recreational use of fentanyl and analogs thereof.
  • the toxicity and/or overdose is caused inadvertently or accidentally when fentanyl and/or an analog thereof is administered as part of a pain management program.
  • emergency situations e.g., situations in which a subject is “found” or identified by a friend, family member, etc., and an ambulance or other emergency service is contacted, or the subject is transported e.g., to an emergency room.
  • the problem of toxicity or overdose may be identified by a medical professional caring for the subject, or even by the subject his-or herself.
  • the subject is thus frequently treated in an emergency setting and administration must be immediate and facile, such as, for example, by: 1) spraying the pharmaceutical into the nose (intranasal ; 2) auto injecting using a pre- filled, ready to use dose of the medication (e.g., by pressing the auto injector against a person’s upper leg; intramuscular or IM); or 3) injecting the naloxone via a needle and syringe (intramuscular or IM). All such means of administration are encompassed by the present methods.
  • the dose of a compound that is administered may be any that is suitable for the particular patient.
  • the dose ranges from about 1 to about 500 mg/kg of body weight, such as about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg/kg, or even more, including all single digit integers between these values.
  • one dose of a pharmaceutical composition is administered as soon as possible after the subject is identified as having had an overdose.
  • the amount administered may generally ranges from about 0.01 to about 500 mg/kg of body weight of the recipient, such as from about 0.05 to 400 mg.kg, or 0.1 to about 300 mg per kg, or about 0.5 to about 200 mg/lg, or about 1 to about 100 mg/kg, such as about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 100 mg/kg, inclusive, including all decimal fractions within these ranges.
  • administration of more than one dose is also encompassed, depending on the amount of fentanyl or analog thereof that was taken by the subject.
  • methods of preventing the death of a suspect who has overdosed and/or who has been poisoned with fentanyl or an analog thereof are provided.
  • Subjects who are treated with the methods described herein are generally mammals, such as humans.
  • veterinary applications of this technology are also encompassed.
  • carfentanil or carfentanyl, sold under the brand name Wildnil® is a very potent opioid analgesic which is used in veterinary medicine to anesthetize large animals such as elephants, rhinoceroses, horses, cattle, various animals living in zoos or preserves, etc.
  • administration may be by tranquilizer dart.
  • one or more of the present compounds may be administered to the animal, usually also by dart or another suitable means (e.g. IM, inhalation, etc.).
  • dart or another suitable means e.g. IM, inhalation, etc.
  • the drugs that cause addiction and/or overdose and/or symptoms of withdrawal that can be treated or prevented as described herein are fentanyl or synthetic congeners of fentanyl.
  • Examples include but are not limited to: fentanyl and its derivatives including but not limited to: Alfentanil; Sufentanil; Remifentanil; Carfentanil; acetylfentanyl; des-methylfentanyl; butyrfentanyl; ocfentanil; acrylfentanyl; para- fluorofentanyl; para-fluoroisobutyrfentanyl; cyclopropyl fentanyl; cis-3-methyl fentanyl; etc.
  • fentanyl and its derivatives including but not limited to: Alfentanil; Sufentanil; Remifentanil; Carfentanil; acetylfentanyl; des-methylfentanyl; butyrfentanyl; ocfentanil; acrylfentanyl; para- fluorofentanyl; para-fluoroisobutyrfentanyl; cyclopropyl fentanyl;
  • the fentanyl overdose or addiction that may be prevented or treated as described herein may be due to the intake of fentanyl alone, or fentanyl that is mixed with or added to other drugs such as heroin, cocaine, methamphetamine, and MDMA (3,4-methylenedioxy methamphetamine, i.e. ecstasy), etc.
  • the compounds disclosed herein are used to prevent or treat addiction to fentanyl and congeners thereof.
  • the compounds can be used in treatment centers, for example, as safe substitutes or replacements for fentanyl and congeners thereof. Typically, in these scenarios, specific doses of the compounds are prescribed for and provided to an addict or recovering addict under trained medical supervision.
  • Dose units of the present compounds can be made using manufacturing methods available in the art and can be of a variety of forms suitable for administration, and can include an enteric coating or other component(s) to facilitate protection from stomach acid, where desired.
  • Dose units can be of any suitable size or shape.
  • the dose unit can be of any shape suitable for enteral administration, e.g., ellipsoid, lenticular, circular, rectangular, cylindrical, and the like.
  • Dose units provided as dry dose units can have a total weight of from about 1 microgram to about 1 gram and can be from about 5 micrograms to 1.5 grams, from about 50 micrograms to 1 gram, from about 100 micrograms to 1 gram, from 50 micrograms to 750 milligrams, and may be from about 1 microgram to 2 grams. Dose units can comprise components in any relative amounts. For example, dose units can be from about 0.1% to 99% by weight of active ingredients per total weight of dose unit. In some embodiments, dose units can be from 10% to 50%, from 20% to 40%, or about 30% by weight of active ingredients per total weight dose unit.
  • Dose units can be provided in a variety of different forms and optionally provided in a manner suitable for storage, for example, a bottle (e.g., with a closure device, such as a cap), a blister pack (e.g., which can provide for enclosure of one or more dose units per blister), a vial, flexible packaging (e.g., sealed Mylar or plastic bags), an ampule (for single dose units in solution), a dropper, thin film, a tube and the like.
  • Containers can include a cap (e.g., screw cap) that is removably connected to the container over an opening through which the dose units disposed within the container can be accessed.
  • Containers can include a seal serve as a tamper-evident and/or tamper- resistant element, which seal is disrupted upon access to a dose unit disposed within the container.
  • seal elements can be, for example, a frangible element that is broken or otherwise modified upon access to a dose unit disposed within the container.
  • frangible seal elements include a seal positioned over a container opening such that access to a dose unit within the container requires disruption of the seal (e.g., by peeling and/or piercing the seal).
  • frangible seal elements include a frangible ring disposed around a container opening and in connection with a cap such that the ring is broken upon opening of the cap to access the dose units in the container.
  • Dry and liquid dose units can be placed in a container (e.g., bottle or package, e.g., a flexible bag) of a size and configuration adapted to maintain stability of dose units over a period during which the dose units are dispensed into a prescription.
  • containers can be sized and configured to contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more single dry or liquid dose units.
  • the containers can be sealed or resealable.
  • the containers can be packaged in a carton or kit (e.g., for shipment from a manufacturer to a pharmacy or other dispensary).
  • Such cartons can be boxes, tubes, or of other configuration, and may be made of any material (e.g., cardboard, plastic, and the like).
  • the packaging system and/or containers disposed therein can have one or more affixed labels (e.g., to provide information such as lot number, dose unit type, manufacturer, and the like).
  • the container can include a moisture barrier and/or light barrier, e.g., to facilitate maintenance of stability of the active ingredients in the dose units contained therein.
  • the dose unit is a dry dose unit
  • the container can include a desiccant pack which is disposed within the container.
  • the container can be adapted to contain a single dose unit or multiples of a dose unit.
  • the container can include a dispensing control mechanism, such as a lock out mechanism that facilitates maintenance of dosing regimen.
  • Dose units can be provided in a container in which they are disposed and may be provided as part of a packaging system or kit (optionally with instructions for use).
  • one or more dose units as described herein can be provided in separate containers, where dose units of different composition are provided in separate containers, and the separate containers disposed within package for dispensing.
  • the mobile phase is acetonitrile/water (90:10) with 0.1% trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • the UV detector was set up at 210 nm. Compound purities were calculated as the percentage peak area of the analyzed compound, and retention times (Rt) were presented in minutes. The purity of all newly synthesized compounds was identified as ⁇ 95%.
  • General Procedure for the synthesis of fentanyl derivatives In a solution of I in anhydrous DCM was added acetic acid and followed by aniline at 0 °C under nitrogen. stirred the reaction mixture for 5 minutes and slowly added sodium triacetoxyhydroborate. stirred the reaction mixture at rt for additional 16h and quenched with adding methanol. Washed the organic layer with water, sat.
  • VZFN032 was prepared following the general procedure as a pale solid in 25% yield.
  • N-(7-benzyl-7-azaspiro[3.5]nonan-2-yl)-N-phenylthiophene-2-carboxamide hydrochloride VZFN035 was prepared following the general procedure as a pale solid in 57% yield.
  • VZFN082 N-(7-(cyclohexylmethyl)-7-azaspiro[3.5]nonan-2-yl)-N-phenylfuran-2-carboxamide hydrochloride
  • N-(7-(cyclohexylmethyl)-7-azaspiro[3.5]nonan-2-yl)-N-phenylthiophene-2-carboxamide hydrochloride (VZFN083) was prepared following the general procedure as a white solid in 36% yield.
  • VZFN085 N-(7-(cyclobutylmethyl)-7-azaspiro[3.5]nonan-3-yl)-N-phenylfuran-3-carboxamide hydrochloride (VZFN085) was prepared following the general procedure as a white solid in 32% yield.
  • VZFN088 N-(7-(cyclopentylmethyl)-7-azaspiro[3.5]nonan-2-yl)-N-phenylthiophene-3- carboxamide hydrochloride (VZFN088) was prepared following the general procedure as a white solid in 30% yield.
  • VZFN089 N-(7-(cyclobutylmethyl)-7-azaspiro[3.5]nonan-2-yl)-N-phenylthiophene-3-carboxamide hydrochloride (VZFN089) was prepared following the general procedure as a white solid in 30% yield.
  • VZFN091 N-(7-(cyclobutylmethyl)-7-azaspiro[3.5]nonan-2-yl)-N-phenylthiophene-2-carboxamide hydrochloride (VZFN091) was prepared following the general procedure as a white solid in 38% yield.
  • N-(7-(cyclopropylmethyl)-7-azaspiro[3.5]nonan-2-yl)-N-phenylthiophene-3- carboxamide hydrochloride (VZFN130) was prepared following the general procedure as a white solid in 40% yield.
  • VZFN133 N-(7-allyl-7-azaspiro[3.5]nonan-2-yl)-N-phenylthiophene-2-carboxamide hydrochloride
  • N-(7-allyl-7-azaspiro[3.5]nonan-2-yl)-N-phenylfuran-2-carboxamide hydrochloride (VZFN136) was prepared following the general procedure as a white solid in 33% yield.
  • VZFN138 N-(7-(cyclopropylmethyl)-7-azaspiro[3.5]nonan-2-yl)-N-phenyl-1H-pyrrole-3- carboxamide hydrochloride
  • N-(7-allyl-7-azaspiro[3.5]nonan-2-yl)-N-phenyl-1H-pyrrole-3-carboxamide hydrochloride (VZFN139) was prepared following the general procedure as a white solid in 15% yield.
  • the mobile phase is acetonitrile/water (90:10) with 0.1% trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • the UV detector was set up at 210 nm. Compound purities were calculated as the percentage peak area of the analyzed compound, and retention times (Rt) were presented in minutes. The purity of all newly synthesized compounds was identified as ⁇ 95%.
  • General Procedure for the synthesis of fentanyl derivatives In a solution of 1 in anhydrous DCM was added acetic acid and followed by aniline at 0 °C under nitrogen. stirred the reaction mixture for 5 minutes and slowly added sodium triacetoxyhydroborate. stirred the reaction mixture at rt for additional 16h and quenched with adding methanol. Washed the organic layer with water, sat.
  • EXAMPLE 6 Chemical synthesis data for 8-member ring system fentanyl analogues 8-member ring system fentanyl derivatives were synthesized according to the general synthesis scheme shown below: Scheme 6.
  • Scheme 6 General Synthesis Scheme for 8-member ring system fentanyl derivatives bath, aniline was added and followed by acetic acid dropwise. The reaction mixture was stirred for 5 minutes and slowly added sodium triacetoxyhydroborate in a portion. The resulting brown reaction mixture was stirred at ambient temperature for additional 16h and quenched with adding methanol, and then diluted with DCM and all contents were transferred to a separatory funnel. The mixture was partitioned by DCM. The organic layer was washed with water, sat.
  • mice 6–8-week 25-35 g male Swiss Webster mice were housed in cages (5 maximal per cage) in animal care quarters and maintained at 22 ⁇ 2 °C on a 12 h light-dark cycle. Food (standard chow) and water were available ad libitum. The mice were brought to the lab (22 ⁇ 2 °C, 12 h light-dark cycle) and allowed 18 h to recover from the transport. The tail-flick test was performed using a water bath with the temperature maintained at 56 ⁇ 0.1°C. The baseline latency (control) was determined before administration of the compounds to the mice, and only mice with a baseline latency of 2 to 4 s were used.
  • AD50 values were calculated using the least-squares linear regression analysis followed by calculation of 95% confidence interval by the Bliss method.
  • Whole body plethysmography.6–8-week 25-35 g male Swiss Webster mice were housed in cages (5 maximal per cage) in animal care quarters and were maintained at 22 ⁇ 2 °C on a reversed 12-hour dark-light cycle. All experiments were conducted in the dark (active) phase. Ventilatory parameters were captured for freely moving mice in individual test chambers using whole-body plethysmography (FinePointe WBP Chamber with Halcyon Technology, Data Sciences International, St. Paul, MN, USA).
  • test chambers 0.5 L volume with adjustable 0.5 L/min room air bias flow
  • the test chambers were housed in a room illuminated by custom- built, 660 nM-emitting T8-style ceiling-mounted light tubes each with 120, 0.2-watt Epistar 2835 SMD LEDs (Benwei Electronics Co., Ltd., Shenzhen, China), a wavelength with limited visibility to mice, to enable maintenance of the dark cycle during testing.
  • the test chambers were continuously supplied 5% CO 2 , 21% O 2 , and balance N 2 (AirGas, Radnor, PA, USA) to minimize variability of baseline ventilatory activity, and to increase the sensitivity and capacity of the assay to detect meaningful differences in ventilation as determined in preliminary tests as well as reported and used by others.
  • Subjects were tested no earlier than at least 1 h after the start of the dark phase to further enhance the capacity to detect perturbations to ventilatory parameters.
  • VZFN093 and VZFN094 did not exhibit a significant increase in minute volume (MVb) at doses up to 32 mg/kg and at 32 mg/kg while they showed a significant increase in tidal volume (TVb) at both 20 min and 10 min post administration. This indicated these compounds have the potential to increase the air volume per respiration cycle. VZFN202 did not show a significant increase in the respiratory parameters observed including MVb, TVb and respiratory rate up to a dose of 30 mg/kg while the trend is positive. EXAMPLE 8.
  • the fentanyl scaffold can be classified into four modifiable moieties, including the N-alkyl chain, piperidine ring, acyl group and aniline ring ( Figure 9). Since the original disclosure of fentanyl by Paul Janssen in 1960, a broad array of fentanyl analogs have been developed by modifying these moieties, primarily seeking analgesics with superior pharmacokinetic properties, onset time, and effective dosage.
  • Fentanyl and its agonist analogs predominantly induce respiratory depression by diminishing the reaction to elevated pCO 2 and reduced pO 2 levels. Consequently, this diminishes the urge to breathe. This subdued respiratory drive leads to a decrease in breathing rate and instances of apnea (temporary cessation of breathing), which, in severe instances, can lead to fatality. Although it did not show any MOR activation potential in the warm-water tail immersion study, compound 3 was studied for its potential liability to cause respiratory depression in mice. This was done in order to further understand the role of the MOR in regard to the stereotypical side effects associated with fentanyl and fentanyl analogs via use of an analog that does not activate the MOR in vivo.
  • WBP Whole-body plethysmography
  • OIRD opioid induced respiratory depression
  • WBP tests the main outcome measures, presented as a percentage relative to the control group, include: 1) Respiratory rate (BPM), which is defined as the number of breaths per minute; 2) Tidal volume (TVb), which is defined as the lung volume that represents the typical amount of air displaced between inhalation and exhalation; and 3) Minute volume (MVb), defined as the volume of air inspired or expired within a minute.
  • BPM Respiratory rate
  • TVb Tidal volume
  • MVb Minute volume
  • minute volume as a representative as it is the product of respiratory rate and tidal volume.
  • the assay was previously validated using 0.15 mg/kg fentanyl. Respiration in freely moving Swiss Webster mice was measured using whole body plethysmography chambers supplied with an air mixture containing 5% CO2. A 10-min baseline respiration period was recorded prior to any compound administration (data not shown). After the acclimatization period, 0.15 mg/kg fentanyl was administered subcutaneously and respiration was recorded for 5 minutes. Following this, vehicle, or 3 mg/kg NLX was administered subcutaneously, and respiration was recorded for a period of 30 minutes. As shown in Figure 13, 3 mg/kg NLX treatment post fentanyl administration resulted in a significant increase in minute volume within 10 minutes. However, this increase lasted for less than 15 minutes.
  • fentanyl and some of its known derivatives induce rapid and profound muscle rigidity. This effect is thought to occur through cerulospinal fibers that are either innervated by or under the control of postsynaptic ⁇ 1A adrenergic receptors ( ⁇ 1A-Adr). Table 3. Binding affinity and functionality of compound 3 and comparator compounds on the ⁇ 1A- and ⁇ 1B-adrenergic receptors.
  • Binding affinity Antagonism function Compound Ki (nM) IC50 (nM) ⁇ 1A-Adr ⁇ 1B- ⁇ 1A-Adr ⁇ 1B-Adr Fentanyl 1100 3660 3690 Compound 110 4750 > 5000 Prazosin 0.13 0.027 4.02 8.7 Thus, to further understand the supposed involvement of the adrenergic system in the pharmacological profile of compound 3, its binding affinity and function at the ⁇ 1A- and ⁇ 1B-Adr were determined.
  • cryo-EM structure of agonist bound ⁇ 2B-Adr (PDB ID 6K41) and the x-ray crystal structure of inverse-agonist bound ⁇ 1B-Adr (PDB ID 7B6W) had the highest sequence identity (39 and 63%, respectively) and homology (57 and 78%, respectively) with the ⁇ 1A-Adr.
  • cryo-EM structure of agonist bound ⁇ 2B-Adr (PDB ID 6K41) showed high sequence identity and homology (39%, 59%) with ⁇ 1B-Adr and was chosen as a template for constructing the homology model of the active conformation of ⁇ 1B-Adr.
  • Multiple sequence alignment revealed that the transmembrane residues were highly conserved between the two template proteins and ⁇ 1A-Adr and ⁇ 1B-Adr (data not shown).
  • Homology models were constructed for all three receptors using SwissModel and model quality was assessed via MolProbity and Protein Structure Analysis (ProSA).
  • fentanyl, and compound 3 were docked in the active and inactive conformations of the ⁇ 1A- and ⁇ 1B- Adr.
  • Protein structures were prepared for docking in Sybylx2.1 and GOLD 2020, a genetic algorithm docking program was used to dock the ligands.
  • the binding site was defined to include all atoms within 10 ⁇ of co-crystallized inverse agonist in the inactive ⁇ 1B-Adr. This binding pocket was retained for docking of the compounds to the active conformation of ⁇ 1B-Adr as well as for both ⁇ 1A-Adr.
  • the ECL2 appeared to be oriented outwards, resulting in a larger binding pocket compared to that seen in the ⁇ 1B-Adr active .
  • This in turn oriented the two glutamate residues away from the binding pocket eliminating the large negative hydrophobic-polar interaction that was seen in case of binding of fentanyl and compound 3 to the ⁇ 1B-Adr active .
  • This allowed for stronger binding interactions of both molecules to the ⁇ 1A-Adr compared to the ⁇ 1B-Adr as reflected by their binding affinities.
  • the ⁇ 1A-and ⁇ 1B-Adr binding pockets have been known to comprise of a conserved orthosteric binding pocket defined Adr bound to epinephrine and, a secondary pocket defined based on the co-crystal structure of the inverse agonist (+)- cyclazosin.
  • the ⁇ 1A-Adr orthosteric binding pocket was largely hydrophobic comprising of residues from TM3, TM6 and TM7 including A103 TM3 , V107 TM3 , W285 TM6 , F288 TM6 , F289 TM6 and F312 TM7 .
  • This orthosteric pocket was conserved between the two receptors with the ⁇ 1B-Adr orthosteric pocket comprising of corresponding residues from TM3, TM6 and TM7 including A122 TM3 , V126 TM3 , W307 TM6 , F310 TM6 , F311 TM6 , F334 TM7 (data not shown). Additionally, the residues E87 TM2 and E180 ECL2 in ⁇ 1A-Adr were also conserved and corresponded to E106 TM2 and E199 ECL2 in ⁇ 1B-Adr (data not shown). Table 4.
  • ChemPLP and HINT scores are of the optimal binding modes of fentanyl and Compound 3 at the two ⁇ -adrenergic receptors.
  • Fentanyl Compound 3 Adr ⁇ 1A active ⁇ 1A inactive ⁇ 1B active ⁇ 1B inactive ⁇ 1A active ⁇ 1A inactive ⁇ 1B active ⁇ 1B inactive In ⁇ 1A-Adr two secondary pockets were observed based on the conformation of the receptor (addressed below). This resulted in a difference in the binding of the compounds and may possibly provide an explanation for their functional activity.
  • Binding of fentanyl and compound 3 to the ⁇ 1A-Adr The piperidine ring of both fentanyl and compound 3 bound in a chair conformation occupying the orthosteric binding pocket while the phenethyl-piperidine nitrogen atom formed electrostatic interactions with D106 TM3 ( Figure 15). However, the binding mode of the phenethyl group of both molecules to the ⁇ 1A-Adr active and ⁇ 1A-Adr inactive were significantly different.
  • phenylfentanil did not reverse the in vivo antinociceptive effects of morphine or fentanyl effectively while it yielded respiratory minute volumes not significantly different from those caused by fentanyl 10 minutes post-administration but were not significantly increased by naloxone. This indicated a potential secondary non-opioidergic mechanism of action. Further studies on the adrenergic system through binding and molecular modeling studies suggested that phenylfentanil may act as an inhibitor on both ⁇ 1A- and ⁇ 1B- adrenergic receptors to potentially induce said respiratory effects.
  • mice Male Swiss-Webster mice (23-35 g, 7 ⁇ 8 weeks, Harlan Laboratories, Indianapolis, IN) were housed five to a cage in animal care quarters maintained at 22 °C on a 12-hour light/dark cycle with food and water available ad libitum. Protocols and procedures were approved by the Institutional Animal Care and Use Committee at Virginia Commonwealth University Medical Center and complied with the recommendations of the International Association for the Study of Pain.
  • the bound radioactive ligand was separated from free radioligand by filtration through GF/B glass fiber filters and rinsed three times with ice-cold wash buffer (50 mM Tris-HCl, pH 7.2) using a Brandel harvester. The results were determined by utilizing a scintillation counter. Specific binding was determined as the difference in binding obtained in the absence and presence of 5 ⁇ M naltrexone. The IC50 values were determined and converted to Ki values using the Cheng–Prusoff equation. Functional assays were conducted in the same cell membranes used for the receptor binding assays.
  • Membrane proteins (10 ⁇ g) were incubated with varying concentrations of drugs, GDP (20 ⁇ M), and 0.1 nM 35 S-GTP[ ⁇ S] in assay buffer for 1.5 h at 30 °C. Nonspecific binding was determined with 20 ⁇ M unlabeled GTP[ ⁇ S].
  • Calcium mobilization assay mMOR-CHO cells were cultured with DMEM/F-12 supplemented with 10% FBS at 37 °C and 5% CO 2 .
  • the cells were transfected with Gqi5 cDNA using Lipofectamine 2000 medium OPTI according to the manufacturer’s recommended procedure. Then the cells were incubated for 4 h before being plated to a clear bottom, black 96-well assay plate at 15,000 cells/well in cell growth media. Cells were ready for calcium mobilization assay after 16-20 h incubation.50 CL of loading buffer was added to each well in the assay plate, followed by 1 hour incubation. The positive control, and varying concentrations of the testing compound were added to a source plate.
  • mice 25-35 g male Swiss Webster mice were housed in cages (5 maximal per cage) in animal care quarters and maintained at 22 ⁇ 2 °C on a 12 h light-dark cycle. Food (standard chow) and water were available ad libitum. The mice were brought to the lab (22 ⁇ 2 °C, 12 h light-dark cycle) and allowed 18 h to recover from the transport. The tail-flick test was performed using a water bath with the temperature maintained at 56 ⁇ 0.1°C. Each mouse was gently wrapped in a cloth with only the tail exposed. Baseline latency was measured before s.c. injection of the compounds.
  • %MPE percentage of maximal possible effect
  • the compound was s.c. injected 5 minutes prior to the agonist administration.
  • Measurement of respiration 6–8-week 25-35 g male Swiss Webster mice were housed in cages (5 maximal per cage) in animal care quarters and were maintained at 22 ⁇ 2 °C on a reversed 12-hour dark-light cycle. All experiments were conducted in the dark (active) phase. Respiration was measured using whole body plethysmography chambers (EMKA Technologies, France) in freely moving mice. The chambers were supplied with an air mixture containing 5% CO2. A 10-min baseline respiration period was recorded prior to any administration. The rate and depth of respiration were recorded and averaged over 1- or 5- min periods.
  • Tidal volume was calculated from the raw inspiration data and expiration data. Minute volume was then calculated as rate x tidal volume. The first compound was administered s.c. and respiration was recorded for 5 minutes. Then respiration was recorded for a period of 30 minutes after the second injection.
  • Statistical Analysis One-way ANOVA followed by the post-hoc Dunnett test were performed to assess significance using Prism 6.0 software (GraphPad Software, San Diego, CA).
  • Homology model construction Due to the unavailability of structures for the active ⁇ 1B- Adr, active ⁇ 1A-Adr and inactive ⁇ 1A-Adr, a database search was performed using the basic local alignment search tool (BLAST) in order to identify a suitable template for homology modeling operation.
  • BLAST basic local alignment search tool
  • the x-ray crystal structure of inverse-agonist bound ⁇ 1B-Adr (PDB ID 7B6W) was used as the inactive conformation of ⁇ 1B-Adr for docking studies.
  • database search was performed using the basic local alignment search tool (BLAST).
  • the cryo-EM structure of agonist bound ⁇ 2B-Adr (PDB ID 6K41) was used as the template for the homology model of the active ⁇ 1A- and ⁇ 1B-Adr while the inverse-agonist bound ⁇ 1B-Adr (PDB ID 7B6W) was used as the template for inactive ⁇ 1A-Adr homology model.
  • the sequence alignment performed using the program Clustal Omega.
  • a distance constraint between the 10-N of the compounds and the carboxylate group of D106 in ⁇ 1A-Adr and D125 in ⁇ 1B-Adr was applied.
  • the molecules were docked into the proteins with a total of 100 iterations.
  • To optimize the structural models for the ligand-protein complexes docking was followed by energy minimization under Tripos Force Field in Sybylx2.1.
  • CHEMPLP score which has been optimized for modeling steric complementarity between ligand and protein along with distance and angle dependent hydrogen bonding, was used to obtain plausible docking poses.
  • HINT Hydrophilicity INTeractions 75
  • Optimal docking poses for each ligand-protein complex were chosen based on highest ChemPLP and HINT scores. Figures were generated using PyMOL version 1.7.4.

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Abstract

L'invention concerne des antagonistes du récepteur opioïde Mu (MOR) qui inversent spécifiquement et efficacement la toxicité aiguë et chronique du fentanyl et de ses analogues. Les antagonistes ont été développés en modifiant le squelette structural du fentanyl et/ou du phénylfentanil. Les antagonistes entrent en compétition avec les fentanyls au niveau du site de liaison MOR et, lorsqu'ils sont liés, ils inversent la toxicité des fentanyls de manière plus efficace et sélective que la naloxone, la naltrexone et d'autres opioïdes de type époxymorphinane.
PCT/US2024/022762 2023-04-04 2024-04-03 Agents d'inversion spécifiques pour traiter la toxicité aiguë et chronique de fentanyls Pending WO2024211360A2 (fr)

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US20220390439A1 (en) * 2019-10-21 2022-12-08 Veriteque Usa, Inc. Fentanyl analogue detection methods and kits thereof
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