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WO2012166891A2 - Composés se fixant au récepteur des opioïdes de type mu - Google Patents

Composés se fixant au récepteur des opioïdes de type mu Download PDF

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Publication number
WO2012166891A2
WO2012166891A2 PCT/US2012/040168 US2012040168W WO2012166891A2 WO 2012166891 A2 WO2012166891 A2 WO 2012166891A2 US 2012040168 W US2012040168 W US 2012040168W WO 2012166891 A2 WO2012166891 A2 WO 2012166891A2
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Prior art keywords
opioid receptor
methyl
pharmaceutically acceptable
compound
compounds
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WO2012166891A3 (fr
Inventor
Luda Diatchenko
William Maixner
Nikolay V. DOKHOLYAN
Feng Ding
Adrian W. R. SEROHIJOS
Shuangye YIN
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ALGYNOMICS Inc
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ALGYNOMICS Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present disclosure relates to mu opioid receptor binding compounds having utility as therapeutic and diagnostic agents, and more specifically to mu opioid receptor binding compounds having ligand affinity for 6-transmembrane and 7-transmembrane structures of the mu opioid receptor.
  • the disclosure also relates to pharmaceutical compositions including such receptor binding compounds, and to methods of making and using such compounds and compositions.
  • the mu( ⁇ )-type opioid receptor is a member of the G-protein-coupled receptor (GPCR) family. It possesses an extracellular N-terminus and an intracellular C-terminus, with seven membrane-spanning domains forming a binding pocket for exogenous drugs. When activated, these seven transmembrane (7TM) domain CPCRs initiate molecular changes that result in inhibition of nerve, immune, and glial cells involved in onset and maintenance of pain.
  • the MOR-1 induces analgesia via pertussis toxin-sensitive inhibitory G protein, which inhibits cAMP formation and calcium conductance and activates potassium conductance, causing hyper-polarization of cells and exerting an inhibitory effect.
  • MOR-1 The major form of MOR-1 binds endogenous and exogenous opioids to mediate analgesia, basal nociception and agonist responses.
  • Opioids are the most commonly prescribed analgesics for treatment of moderate to severe pain.
  • clinically used opioids such as morphine are generally extremely effective analgesic agents, there is a significant degree of individual variation in the degree of opioid analgesia and adverse side effects, including nausea, vomiting, sedation, cognitive impairment, constipation, tolerance, dependence, neurotoxicity, life-threatening respiratory depression, and paradoxical hyperalgesia, and such side effects may become severely exacerbated by prolonged use of opioids.
  • Decades of research have been devoted to developing an opioid analgesic that has the analgesic efficacy of morphine but is devoid of its adverse effects.
  • MOR-1 activation associated with binding of opioid compounds can involve cellular excitation and inhibition effects.
  • Excitatory effects evidenced by increased calcium levels are associated with opioid side effects, while lowered calcium levels incident to MOR-1 activation are associated with cellular inhibitory effects mediating analgesia.
  • 7TM mu-opioid receptor agonists therefore include desirable analgesics
  • 7TM mu- opioid receptor antagonists include agents that are useful in treatment of opioid addiction or in modulating side effects.
  • 6TM mu-opioid receptor agonists increase nociceptive effects
  • 6TM mu-opioid receptor antagonists are useful in blocking cellular excitatory effects and promoting cellular inhibitory effects that mediate analgesia.
  • MOR-1 receptor binding ligands As therapeutic agents and/or as analytical and diagnostic agents.
  • the present disclosure relates to MOR-1 receptor binding compounds, and to use of same as therapeutic, analytical and diagnostic agents, as well as pharmaceutical compositions comprising such compounds, and methods of making and using such compounds and compositions.
  • the present disclosure relates to mu opioid receptor binding compounds having utility as therapeutic and diagnostic agents, and more specifically to mu opioid receptor binding compounds having ligand affinity for 6-transmembrane and 7-transmembrane structures of the mu opioid receptor.
  • the disclosure also relates to pharmaceutical compositions including such receptor binding compounds, and to methods of making and using such compounds and compositions.
  • the disclosure relates to a pharmaceutical composition, comprising (i) a mu opioid receptor modulating compound selected from the group consisting of Group I compounds and their pharmaceutically acceptable derivatives, (ii) a pharmaceutically acceptable carrier, and (iii) optionally, another therapeutic agent.
  • a pharmaceutical composition comprising (i) a mu opioid receptor modulating compound binding a 7TM structure of said receptor, selected from the group consisting of
  • the disclosure relates to a pharmaceutical composition, comprising (i) a mu opioid receptor modulating compound binding a 6TM structure of said receptor, selected from the group consisting of
  • a further aspect of the disclosure relates to a pharmaceutical composition, comprising (i) a mu opioid receptor modulating compound binding both 6TM and 7TM structures of said receptor, selected from the group consisting of
  • a still further aspect of the disclosure relates to a method of modulating mu opioid receptor response in a subject in need thereof, comprising administering to the subject an effective amount for said response modulation of a mu opioid receptor modulating compound selected from the group consisting of Group I compounds and their pharmaceutically acceptable derivatives.
  • Yet another aspect of the disclosure relates to a method of modulating mu opioid receptor response in a subject in need thereof, comprising administering to the subject an effective amount for said response modulation of a mu opioid receptor modulating compound binding a 7TM structure of said receptor, selected from the group consisting of
  • a further aspect of the disclosure relates to a method of modulating mu opioid receptor response in a subject in need thereof, comprising administering to the subject an effective amount for said response modulation of a mu opioid receptor modulating compound binding a 6TM structure of said receptor, selected from the group consisting of
  • the disclosure in a further aspect relates to a method of modulating mu opioid receptor response in a subject in need thereof, comprising administering to the subject an effective amount for said response modulation of a mu opioid receptor modulating compound binding both 6TM and 7TM structures of said receptor, selected from the group consisting of
  • Yet another aspect of the disclosure relates to a pharmaceutical composition, comprising (i) a mu opioid receptor modulating compound selected from the group consisting of Matching Compounds and their pharmaceutically acceptable derivatives, (ii) a pharmaceutically acceptable carrier, and (iii) optionally, another therapeutic agent.
  • Another aspect of the disclosure relates to a method of modulating mu opioid receptor response in a subject in need thereof, comprising administering to the subject an effective amount for said response modulation of a mu opioid receptor modulating compound selected from the group consisting of Matching Compounds and their pharmaceutically acceptable derivatives.
  • a still further aspect of the disclosure relates to a therapeutic cocktail formulation, including (i) at least one Group I compound, Matching Compound, or pharmaceutically acceptable derivative thereof, and (ii) at least one compound selected from the group consisting of morphine, (+)- morphine, methadone, (+)-methadone, 3-methoxynaltrexone, etorphine, and naltrexone.
  • FIG. 1A depicts a human mu opioid receptor model exhibiting a seven-transmembrane- helix topology conserved among G-protein coupled receptors (GPCRs), wherein N and C-termini are colored blue and red, respectively.
  • GPCRs G-protein coupled receptors
  • FIG. IB is a Ramachandran plot mapping the Phi and Psi torsion angles of each residue. Regions bounded by dark blue are allowed conformations while those bounded by cyan are favored conformations.
  • FIG. 2A depicts the mapping of mutations in the mu opioid receptor model, showing sites where mutations significantly affect ligand binding.
  • FIG. 2B depicts the mapping of mutations in the mu opioid receptor model that do not significantly affect ligand binding. These include V128A (TM II); T139E, I140L, I144A, I146L, and N152A (TM III); I200V and V204I (TM IV); K235 to R, A, H, and L (TM V); and H299 to Q and N (TM VI). In the mu opioid receptor model, these residues are either far or their side chains face away from the ligand-binding pocket.
  • FIG. 3 is a depiction of the calculated surface charge distribution of the mu opioid receptor model.
  • FIG. 4 is a depiction of the packing of a bilayer of the lipid DPPC (dipalmitoylmphosphatidylcholine) around the mu opioid receptor.
  • FIG. 5 shows the conformational result of an equilibrium simulation performed on the mu opioid receptor model embedded in the DPPC bilayer for 8 ns, with the final structure (green) being ⁇ 3 A root mean square deviation (RMSD) with respect to the starting conformation (cyan).
  • FIG. 6 is a graph of RMSD as a function of time in nanoseconds, for such molecular dynamics simulation of FIG. 5, showing that the model is stable during the molecular dynamics simulations.
  • FIG. 7 shows the structure of the 7TM variant, and the first transmembrane helix HI, which does not directly interact with bound morphine.
  • FIG. 8 shows the putative binding pocket of the human mu opioid receptor 6TM variant.
  • FIG. 9 shows the 6TM variant molecular dynamics simulation.
  • FIG. 10 is a graph of the root mean square deviation (RMSD) of the protein backbone with respect to the initial conformation of the 6TM structure.
  • RMSD root mean square deviation
  • FIG. 11 shows the superposition of the human mu opioid receptor 6TM variant conformation before simulation (in cyan color) and after simulation (in green color).
  • FIG. 12 shows a corresponding superposition view from the extracellular side of the superposition of the human mu opioid receptor 6TM variant conformation before simulation (in cyan color) and after simulation (in green color).
  • FIG. 13 is a plot of the root mean square fluctuations (RMSF), in Angstroms, for each residue during the simulation of the 7TM variant with and without morphine.
  • RMSF root mean square fluctuations
  • FIG. 14 is a depiction of the 7TM variant with and without morphine, with the RMSF values mapped onto the protein structure.
  • FIG. 15 is a plot of the root mean square fluctuations (RMSF), in Angstroms, for each residue during the simulation of the 6TM variant with and without morphine.
  • RMSF root mean square fluctuations
  • FIG. 16 is a depiction of the 6TM variant with and without morphine, with the RMSF values mapped onto the protein structure.
  • FIG. 17 shows the binding pocket residues with their calculated contact frequencies for the 7TM variant (left panel) and the 6TM variant (right panel), together with a contact probability scale shown at the far right for the 7TM and 6TM panels.
  • FIG. 18 shows residues specific to both 6TM and 7TM variant binding pockets.
  • FIG. 19 shows mutation sites that affect binding to the 7TM variant more than to the 6TM variant.
  • FIG. 20 shows mutation sites that affect binding to the 6TM variant more than to the 7TM variant.
  • FIG. 21 is a schematic flow chart for the virtual screening process for identifying binding ligands to a protein target, as utilized to identify modulator compounds for 7TM and 6TM human mu opioid receptor variants.
  • the present disclosure relates to MOR-1 receptor binding compounds, including agonist and antagonist compounds effective to modulate MOR-1 receptor activity.
  • Such compounds include receptor modulating compounds having binding affinity for 6-transmembrane (6TM) and 7- transmembrane (7TM) structures of the mu opioid receptor.
  • the disclosure also relates to compositions containing such compounds, and to methods of making and using such compounds and compositions.
  • the mu opioid receptor 6TM binding compounds include 6TM agonists that increase nociceptive effects and 6TM antagonists that mediate analgesia.
  • the mu opioid receptor 7TM binding compounds include 7TM agonists that mediate analgesia, and 7TM antagonists that increase nociceptive effects.
  • the present disclosure further relates to pharmaceutical compositions in which mu opioid receptor binding compounds are utilized in combination with other therapeutic agents, such as therapeutic agents that enhance therapeutic efficacy, such as by increasing analgesia, decreasing side effects, e.g., respiratory depression, otherwise incident to administration of opioid receptor binding compounds, decreasing tolerance to mu opioid receptor binding compounds, etc.
  • therapeutic agents that enhance therapeutic efficacy such as by increasing analgesia, decreasing side effects, e.g., respiratory depression, otherwise incident to administration of opioid receptor binding compounds, decreasing tolerance to mu opioid receptor binding compounds, etc.
  • Compounds of the present disclosure may also be utilized in combination with therapeutic agents that potentiate opioid- mediated analgesia so that lower dosage of the compounds is possible to produce somatosensory or other therapeutic benefit.
  • ester substituents in compounds including same may be replaced with an amide or thioamide moiety to increase the in vivo stability.
  • Carbamate, thiocarbamate, urea, thiourea, ether, and thioether moieties can also be substituted for ester moieties.
  • Aryl rings can be replaced with heteroaryl rings, such as thiophene rings in these compounds.
  • the compounds disclosed herein can optionally be substituted with a morpholinyl or piperidinyl moiety, which can be desirable to increase hydrophilicity.
  • Novel compounds may also be formed in a combination of substituents which creates a chiral center or another form of an isomeric center.
  • the compound may variously exist as a racemic mixture, a pure enantiomer, and any enantiomerically enriched mixture.
  • the compounds can occur in varying degrees of enantiomeric excess, and racemic mixtures can be purified using known chiral separation techniques.
  • the compounds can be in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts).
  • Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, dichloroacetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with an acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium; ammonium salt; organic basic salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, and ⁇ , ⁇ '-dibenzylethylenediamine; and salts with a basic amino acid such as lysine and arginine.
  • the salts can be in some cases hydrates or ethanol solvates. The
  • the compounds described herein can be derivatized in any suitable manner, e.g., by formation of salts, esters, solvates, polymorphs or prodrugs of the specifically disclosed compounds.
  • Compounds including at least one aryl or heteroaryl ring can be substituted on one or more of these rings with one or more substituents.
  • substituents can be readily realized. Such substituents can provide useful properties in and of themselves or facilitate further synthetic elaboration.
  • Benzene rings (and pyridine, pyrimidine, pyrazine, and other heteroaryl rings) can be substituted using known chemistry.
  • the nitro group on nitrobenzene can be reacted with sodium nitrite to form the diazonium salt, and the diazonium salt manipulated to form the various substituents on a benzene ring.
  • Diazonium salts can be halogenated using various known procedures, which vary depending on the particular halogen.
  • suitable reagents include bromine/water in concentrated HBr, thionyl chloride, pyr-ICl, fluorine and Amberlyst-A.
  • a number of other analogs, bearing substituents in the diazotized position, can be synthesized from the corresponding amino compounds, via the diazocyclopentadiene intermediate.
  • the diazo compounds can be prepared using known chemistry, for example, as described above.
  • Nitro derivatives can be reduced to the amine compound by reaction with a nitrite salt, typically in the presence of an acid.
  • Other substituted analogs can be produced from diazonium salt intermediates, including, but are not limited to, hydroxy, alkoxy, fluoro, chloro, iodo, cyano, and mercapto, using general techniques known to those of skill in the art.
  • hydroxy-aromatic/heteroaromatic analogs can be prepared by reacting the diazonium salt intermediate with water.
  • Halogens on an aryl or heteroaryl rings can be converted to Grignard or organolithium reagents, which in turn can be reacted with suitable aldehyde or ketone to form alcohol-containing side chains.
  • alkoxy analogs can be made by reacting the diazo compounds with alcohols.
  • the diazo compounds can also be used to synthesize cyano or halo compounds, as will be known to those skilled in the art. Mercapto substitutions can be obtained using techniques described in Hoffman et al., . Med. Chem. 36: 953 (1993).
  • the mercaptan so generated can, in turn, be converted to an alkylthio substitutuent by reaction with sodium hydride and an appropriate alkyl bromide. Subsequent oxidation would then provide a sulfone.
  • Acylamido analogs of the compounds can be prepared by reacting the corresponding amino compounds with an appropriate acid anhydride or acid chloride using techniques known to those skilled in the art of organic synthesis.
  • Hydroxy-substituted analogs can be used to prepare corresponding alkanoyloxy- substituted compounds by reaction with the appropriate acid, acid chloride, or acid anhydride.
  • the hydroxy compounds are precursors of both the aryloxy and heteroaryloxy via nucleophilic aromatic substitution at electron deficient aromatic rings.
  • Ether derivatives can also be prepared from the hydroxy compounds by alkylation with alkyl halides and a suitable base or via Mitsunobu chemistry, in which a trialkyl- or triarylphosphine and diethyl azodicarboxylate are typically used. See Hughes, Org. React. (N. Y.) 42: 335 (1992) and Hughes, Org. Prep. Proced. Int. 28: 127 (1996) for typical Mitsunobu conditions.
  • Cyano-substituted analogs can be hydrolyzed to afford the corresponding carboxamido- substituted compounds. Further hydrolysis results in formation of the corresponding carboxylic acid- substituted analogs. Reduction of the cyano-substituted analogs with lithium aluminum hydride yields the corresponding aminomethyl analogs. Acyl-substituted analogs can be prepared from corresponding carboxylic acid-substituted analogs by reaction with an appropriate alkyllithium using techniques known to those skilled in the art of organic synthesis.
  • Carboxylic acid-substituted analogs can be converted to the corresponding esters by reaction with an appropriate alcohol and acid catalyst.
  • Compounds with an ester group can be reduced with sodium borohydride or lithium aluminum hydride to produce the corresponding hydroxymethyl- substituted analogs.
  • These analogs in turn can be converted to compounds bearing an ether moiety by reaction with sodium hydride and an appropriate alkyl halide, using conventional techniques.
  • the hydroxymethyl-substituted analogs can be reacted with tosyl chloride to provide the corresponding tosyloxymethyl analogs, which can be converted to the corresponding alkylaminoacyl analogs by sequential treatment with thionyl chloride and an appropriate alkylamine.
  • amides are known to readily undergo nucleophilic acyl substitution to produce ketones.
  • Hydroxy-substituted analogs can be used to prepare N-alkyl- or N-arylcarbamoyloxy- substituted compounds by reaction with N-alkyl- or N-arylisocyanates.
  • Amino-substituted analogs can be used to prepare alkoxycarboxamido-substituted compounds and urea derivatives by reaction with alkyl chloroformate esters and N-alkyl- or N-arylisocyanates, respectively, using techniques known to those skilled in the art of organic synthesis.
  • Compounds of the present disclosure can be utilized to modulate mu opioid receptor activity, and to mediate analgesia or nociceptive response, or to elicit or combat other receptor response, depending on the appertaining agonistic or antagonistic character of such compounds.
  • the compounds can be used to characterize tissues as to presence and density of mu opioid receptors, or 6TM or 7TM structures of such receptors.
  • the compounds can be used diagnostically to predict or determine pain sensitivity, to modify pain sensitivity, or to characterize and treat somatosensory disorders.
  • Such modulation of mu opioid receptor activity within the scope of the present disclosure also includes modulation of splice variant forms of the human mu opioid receptor, such as the six transmembrane isoforms encoded by MOR-1K1 and MOR-1K2.
  • MOR-1 splice variant forms are more fully described in International Patent Application PCT/US 2009/054300 filed August 19, 2009, the disclosure of which is hereby incorporated herein by reference in its entirety, for all purposes.
  • the present disclosure contemplates use of the compounds described herein, in pharmaceutical formulations for therapeutic administration.
  • the active pharmaceutical ingredient preferably is utilized together with one or more pharmaceutically acceptable carrier(s) therefor and optionally any other therapeutic ingredients.
  • the carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and therapeutically beneficial to the recipient thereof.
  • the active pharmaceutical ingredient is provided in an amount effective to achieve the desired pharmacological effect, and in a quantity appropriate to achieve the desired dose on a daily or other temporal basis.
  • the present disclosure contemplates a method of treating an animal subject having or latently susceptible to a disease state or physiological condition for which a compound of the present disclosure is beneficially administered, comprising administering to such subject an effective amount of a compound of the present invention that is therapeutically effective for said condition or disease state.
  • Subjects to be treated by the compounds of the present invention include both human and non-human animal (e.g., bird, dog, cat, cow, horse) subjects, and are preferably mammalian subjects, and most preferably human subjects.
  • animal subjects may be administered compounds of the present invention at any suitable therapeutically effective and safe dosages, as may readily be determined within the skill of the art and without undue experimentation, based on the disclosure herein.
  • compounds of the present invention may be administered in specific embodiments at a dosage between about 0.01 and 200 mg/kg, preferably between about 1 and 90 mg/kg, and more preferably between about 10 and 80 mg/kg.
  • the compounds of the present disclosure may be administered per se as well as in the form of pharmaceutically acceptable esters, salts, and other physiologically functional derivatives thereof.
  • the compounds may be utilized in a wide variety of pharmaceutical formulations, both for veterinary and for human medical use, which comprise as the active pharmaceutical ingredient one or more compound(s) of the present disclosure.
  • the formulations include those suitable for parenteral as well as non-parenteral administration, and specific administration modalities include, but are not limited to, oral, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and intra-uterine administration.
  • Formulations suitable for oral and parenteral administration are preferred, with formulations suitable for oral administration most preferred.
  • the formulation advantageously may be administered orally or parenterally.
  • a compound of the present disclosure is employed in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.
  • the compound when a compound of the present disclosure is utilized directly in the form of a powdered solid, the compound may advantageously be administered orally. Alternatively, it may be administered bronchially, via nebulization of the powder in a carrier gas, to form a gaseous dispersion of the powder that is inspired by the patient from a breathing circuit comprising a suitable nebulizer device.
  • the formulations comprising a compound of the present disclosure may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing a compound of the present invention into association with a carrier that constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing a compound of the present disclosure into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation.
  • Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of a compound of the present disclosure as a powder or granules, or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or a draught.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent.
  • Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
  • a syrup may be made by adding a compound of the present disclosure to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s).
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include, for example, flavorings, suitable preservatives, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
  • Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of a compound of the present invention, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution).
  • Such formulations may include suspending agents and thickening agents or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit- dose or multi-dose form.
  • Nasal spray formulations comprise purified aqueous solutions of a compound of the present invention with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucus membranes.
  • Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acid.
  • Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye.
  • Topical formulations comprise a compound of the present disclosure dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
  • media such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.
  • specific formulations may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
  • active pharmaceutical compounds of the present disclosure can be used in therapeutic compositions that may further comprise one or more other medicaments, including, by way of example, but not limited to anti-inflammatory agents such as mesalamine, sulfasalazine, balsalazide, and olsalazine; immunomodulators such as azathioprine, 6-mercaptorpurine, cyclosporine and methotrexate; steroidal compounds such as corticosteroids; and antibiotics such as metronidazole and ciprofloxacin, as well as other ingredients such as excipients, disintegrants, release modifiers, etc.
  • anti-inflammatory agents such as mesalamine, sulfasalazine, balsalazide, and olsalazine
  • immunomodulators such as azathioprine, 6-mercaptorpurine, cyclosporine and methotrexate
  • steroidal compounds such as corticosteroids
  • antibiotics such as metroni
  • Group I compounds Representative compounds of the present disclosure (hereafter referred to as “Group I compounds” for ease of reference) include:
  • preferred 7TM receptor binding compounds (i) 2-(3-methylpiperidin- 1 -yl)-2-(naphthalene- 1 -yl)ethan- 1 -amine
  • preferred 6TM binding compounds include
  • preferred promiscuous ligand compounds binding to both 6TM and 7TM structures of mu opioid receptor include
  • Compound A is prepared beginning with condensation of 2-amino-4-phenyl-3- thiophenecarboxylic acid and chloroacetonitrile using dry HCl gas in anhydrous 1,4-dioxane to provide an intermediate 2-(chloromethyl)-5-phenylthieno[2,3-d]pyrimidin-4-one.
  • the resulting intermediate chloride is reacted with morphiline in a dry organic solvent such as DMF in the presence of an organic base such as triethylamine or an inorganic base such as sodium carbonate or the like, to provide intermediate 2-(morphilinomethyl)-5-phenylthieno[2,3- d]pyrimidin-4-one.
  • a dry organic solvent such as DMF
  • an organic base such as triethylamine or an inorganic base such as sodium carbonate or the like
  • the pyrimidin-4-one is further reacted to provide a 4-chloropyrimidine.
  • reaction of 2-(morphilinomethyl)-5-phenylthieno[2,3-d]pyrimidin-4-one with phosphorus oxychloride in DMF yields 4-chloro-2-(morphilinomethyl)-5-phenylthieno[2,3-d]pyrimidine.
  • Compound A is produced by reaction of the 4-chlorothieno[2,3-d]pyrimidine with 5-(3- fluorophenyl-1H- 1,2,3, 4-tetrazole in a polar solvent such as DMF, in the presence of a base, e.g., an organic base such as triethyl amine, or, more preferably, an inorganic base such as sodium carbonate or cesium carbonate.
  • a base e.g., an organic base such as triethyl amine, or, more preferably, an inorganic base such as sodium carbonate or cesium carbonate.
  • Compound B is synthesized through the condensation of 2-naphthol and dimethyl acetylenedicarboxylate mediated by triethyl phosphite in DCM, to provide methyl 3-oxo-1H,2H,3H- naphtho[2, 1 -b]pyran- 1 -carboxylate.
  • the methyl ester can be selectively reduced with diisobutyl aluminum hydride (DIBAL) at -78° C to provide the 3-oxo-1H,2H,3H-naphtho[2,l-b]pyran-1-methyl alcohol.
  • DIBAL diisobutyl aluminum hydride
  • the alcohol can be further subjected to an activation/displacement sequence using any number of activating agents known to the art, such as trifluoromethanesulfonyl chloride and DIPEA.
  • activating agents such as trifluoromethanesulfonyl chloride and DIPEA.
  • the resulting triflate may, without isolation, be reacted in situ with l-(2-pyridyl)piperazine to yield Compound B.
  • Compound C is synthesized from tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate through reaction with 3,4-difluorobenzyl bromide in DMF with added Cs 2 C0 3 to provide tert-butyl 2- [(3,4-difluorophenyl)methyl]-2,7-diazaspiro[4.5]decane-7-carboxylate.
  • the tert-butylcarboxy protecting group is subsequently removed through treatment with organic acid such as trifluoroacetic acid, or mineral acid such as HCl, to provide 2- [(3, 4- difluorophenyl) methyl] -2,7 -diazaspiro [4.5] decane .
  • organic acid such as trifluoroacetic acid, or mineral acid such as HCl
  • Compound D can be synthesized commencing with l-adamantan-2-yl-piperazine through alkylation with ethyl bromoacetate in DMF, with Cs 2 C0 3 or Na 2 C0 3 added, yielding ethyl 2-[4- (adamantan-2-yl)piperazin- 1 -yl] acetate.
  • Compound E is formed beginning with condensation between commercial 3-chloro-1H- indole -2 -carboxylic acid and 4-hydroxy piperadine mediated by dehydrating agent such as HCTU in the presence of DIPEA to provide l-[(3-chloro-1H-indol-2-yl)carbonyl]piperidin-4-ol.
  • Azide is then converted to a 1,2,3-triazole moiety through reaction with the alkyne propargylaldehyde diethyl acetal to produce 3-chloro-2-( ⁇ 4-[4-(diethoxymethyl)-1H-1,2,3-triazol-1- yl]piperadin-1-yl ⁇ methyl)1H-indol.
  • the diethyl acetal can subsequently be hydrolyzed with dilute acid such as HCl in THF/H 2 0 to secure the corresponding aldehyde.
  • Compound F can be synthesized starting with the condensation reaction between octahydro-2-benzofuran-1,3-dione and 2,3-dihydro-1H-indole to provide the carboxylic acid 2-[(2,3- dihydro- 1 H-indol- 1 -yl)carbonyl]cyclohexane- 1 -carboxylic acid.
  • Formula G compound can be synthesized starting with a double alkylation reaction between 4-fluorophenyl acetonitrile and 2-chloroethyl chloromethyl ether using a strong base such as NaH, in a polar solvent like DMF, or NMP, to provide 3-(4-fluorophenyl)oxolane-3-carbonitrile.
  • the nitrile functional group is subsequently hydrolyzed to a carboxylic acid using H 2 S0 4 .
  • the resulting 3-(4-fluorophenyl)oxolane-3-carboxylic acid is condensed with N-(2- aminoethyl)-4-methylpyridin-2-amine using a dehydrating agent such as EDC with added DIPEA to obtain amide 3-(4-fluorophenyl)N- ⁇ 2-[(4-methylpyridin-2-yl)annno]ethyl ⁇ oxolane-3-carboxamide.
  • Compound H can be obtained from commercial 4-(4-bromophenyl)-2 -thiazolamine, utilizing condensation between the thiazolamine and bromoacetic acid mediated by EDC/DIPEA to yield 2-bromo-N-[4-(4-bromophenyl)-1,3-thiazol-2yl]acetamide, followed by displacement of the bromide with dibenzyl amine using Cs 2 C0 3 in dry DMF to yield Compound H.
  • Compound I is synthesized starting from a condensation between 2-aminopyridine and ethyl bromopyruvate to provide ethyl imidazo[1,2-a]pyridine-2-carboxylate.
  • Formylation at the 3 position of the imidazo[1,2-a]pyridine with phosphorus oxychloride in dimethyl sulfoxide (DMF) provides ethyl 3-formylimidazo[1,2-a]pyridine-2-carboxylate.
  • Compound J is included for comparative basis. This compound is available as Nalmefene, CAS RN [55096-26-9], commercially available from Somaxon Pharmaceuticals, Inc. (San Diego, California, USA) and is a mu opioid antagonist having similar structure to naltrexone.
  • Compound K can be synthesized starting with a three -component, one -pot, condensation involving naphthalene carboxyaldehyde, 3-methyl piperidine and sodium cyanide mediated by aqueous NaHS0 3.
  • Compound L can be synthesized starting from a condensation between 4-chlororesorcinol and ethyl 2-oxocyclopentanecarboxylate using dilute H 2 S0 4 . to yield 8-chloro-7-hydroxy- 1H,2H,3H,4H-cyclopenta[c]chromen-4-one.
  • Aminomethylation at the 6-position occurs with dilute acid and the aminal-dimer derived from (tetrahydrofuran-3-yl)methylamine to yield Compound L.
  • Compound M can be synthesized from a one-step condensation between l-(1H-indol-2- yl)-2-methyl-propan-2-amine and 2,2,6,6-tetramethylpiperidin-4-one using concentrated HCl in ethanol.
  • Compound N can be synthesized commencing with a condensation between adamantylamine and 2-(tert-butyldimethylsiloxy)acetic acid utilizing EDC as a dehydrating agent DIPEA as organic base. Subsequent removal of the silyl protecting group with tetra butyl ammonium fluoride (TBAF) in tetrahydrofuran (THF) provides intermediate N-(adaman-2-yl)-2 -hydroxy acetamide.
  • EDC a dehydrating agent
  • DIPEA dehydrating agent
  • Compound O is advantageously formed commencing with a condensation between 2- phenoxyaniline and bromoacetic acid mediated by a dehydrating agent such as EDC.
  • Compound P is synthesized commencing with acylation of 2-amino-5-cyclohexyl-1,3,4- thiadiazole with bromoacetic acid with the use of EDC and DIPEA.
  • Compound P is obtained through the reaction of the resulting 2-bromo-N-(5-cyclohexyl- 1,3,4-thiadiazole-2-yl)acetamide and dibenzylamine in the presence of Cs 2 C0 3 in anhydrous DMF.
  • Compound Q can be synthesized starting with the condensation reaction between octahydro-2-benzofuran-l,3-dione and 2,3-dihydro-1H-indole to provide the carboxylic acid 2-[(2,3- dihydro- 1 H-indol- 1 -yl)carbonyl]cyclohexane- 1 -carboxylic acid.
  • Compound R can be carried out through a reductive animation between 3-[l,l '-biphenyl]-4-yl-1H-pyrazole-4-carboxaldehyde and l-(1H-l,2,4-triazol-5-yl)ethyl amine using NaCNBH 3 .
  • l-(1H-l,2,4-triazol-5-yl)ethyl amine can be synthesized through a three-component condensation involving Boc-alaninamide, dimethylformamide (DMF) dimethyl acetal and hydrazine hydrate.
  • the resulting tert-butyl N-[l-(1H-l,2,4-triazol-5-yl)ethyl]carbamate can be deprotected with trifluoroacetic acid (TFA) in dichloromethane (DCM) then free-based with aqueous NaHC0 3 to provide free amine for condensation.
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • Compound S can be generated through a dehydrative condensation between the carbaldehyde and 1,2,3,4-tetrahydro-1-isoquinolinemethanamine.
  • Compound T can be achieved through the condensation between m- toluidine and 2-(tert-butyldimethylsiloxy)propionic acid in the presence of EDC and DIPEA. Removal of the silyl protecting group with TBAF/THF provides 2-hydroxy-N-(2- methylphenyl)propanamide.
  • Compound U is produced through the sulfonylation of piperidine-4-carboxylic acid methyl ester using 2-naphthalenesulfonyl chloride in the presence of pyridine in dichloromethane (DCM) to provide methyl l-(naphthalene-2-sulfonyl)piperidine-4-carboxylate.
  • DCM dichloromethane
  • Another aspect of the invention relates to mu opioid receptor binding compounds that fit the in silico model of the mu opioid receptor and the 6-transmembrane and 7-transmembrane structures of the mu opioid receptor, as described more fully hereinafter.
  • Such compounds exhibiting ligand affinity in the in silico model hereafter referred to as Matching Compounds as well as the pharmaceutically acceptable derivatives of such compounds exhibiting such ligand affinity, constitute a further class of mu opioid receptor binding compounds contemplated by the invention.
  • Matching Compounds can be derivatized as previously described herein, to form corresponding derivatives such as salts, esters, solvates, polymorphs, prodrugs, etc.
  • the invention contemplates a therapeutic composition
  • a therapeutic composition comprising (i) a mu opioid receptor modulating compound selected from the group consisting of Matching Compounds and their pharmaceutically acceptable derivatives, (ii) a pharmaceutically acceptable carrier, and (iii) optionally, another therapeutic agent.
  • Such therapeutic composition can be employed in a method of modulating mu opioid receptor response in a subject in need thereof, comprising administering to the subject an effective amount for said response modulation of a mu opioid receptor modulating compound selected from the group consisting of Matching Compounds and their pharmaceutically acceptable derivatives.
  • the invention in a still further aspect relates to a therapeutic cocktail formulation, including (i) at least one Group I compound, Matching Compound, or pharmaceutically acceptable derivative thereof, and (ii) at least one compound selected from the group consisting of morphine, (+)- morphine, methadone, (+)-methadone, 3-methoxynaltrexone, etorphine, and naltrexone.
  • FIG. 1A depicts a human mu opioid receptor model exhibiting a seven-transmembrane -helix topology conserved among G-protein coupled receptors (GPCRs). N and C-termini are colored blue and red, respectively.
  • FIG. IB is a Ramachandran plot mapping the Phi and Psi torsion angles of each residue. Regions bounded by dark blue are allowed conformations while those bounded by cyan are favored conformations.
  • the ligand binding pocket of the OPRM1 model was also validated by testing its binding to a list of known OPRM1 -binding ligands.
  • the ⁇ -opioid selective agonist morphine, the ⁇ -opioid- selective antagonist ⁇ -funaltrexamine, and the non-selective opioid agonists diphrenorphine, naloxone, and naltrexone were docked to the human mu opioid receptor model, exhibiting similar docking poses in the binding pocket.
  • FIG. 2A depicts the mapping of mutations in the mu opioid receptor model, showing sites where mutations significantly affect ligand binding.
  • mutating D149 (TM III) to glutamic acid and Y326 (TM VII) to phenylalanine significantly reduces morphine binding by 100- to 1000- fold.
  • a GPCR conserved disulfide bond is shown between C142/C219.
  • D149 and Y326 mediate morphine binding in the putative binding site.
  • Substituting D116 (TM II) to either asparagine, glutamic acid, or alanine also shows a 100- to 1000-fold reduction in binding.
  • D116 faces the ligand-binding pocket, it does not directly interact with the ligand. Accordingly, mutations in this site may induce mu opioid receptor helix repacking.
  • FIG. 4 is a depiction of the packing of a bilayer of the lipid DPPC (dipalmitoylmphosphatidylcholine) around the mu opioid receptor.
  • DPPC dipalmitoylmphosphatidylcholine
  • FIG. 5 shows the conformational result of an equilibrium simulation performed on the mu opioid receptor model embedded in the DPPC bilayer for 8 ns, with the final structure (green) being ⁇ 3 A root mean square deviation (RMSD) with respect to the starting conformation (cyan), suggesting no major conformational change occurred.
  • RMSD root mean square deviation
  • cyan the starting conformation
  • FIG. 6 is a graph of RMSD as a function of time in nanoseconds, for such molecular dynamics simulation of FIG. 5, showing that the model is stable during the molecular dynamics simulations.
  • the mu opioid receptor model exhibits valid conformations, comparable to known crystal structures of other GPCRs.
  • the predicted morphine lowest energy pose recapitulates experimental binding affinity.
  • Known mu opioid receptor binders exhibit similar docking poses.
  • the GPCR conserved disulfide bond between C142/C219 is preserved in the mu opioid receptor model.
  • the hydrophobic surface packs with lipid bilayer, and charged surfaces are exposed to water.
  • the model is stable during molecular dynamics simulations.
  • a corresponding in silico modeling effort was carried out to model the 6TM variant of the human mu opioid receptor.
  • the approach to modeling the human mu opioid receptor 6TM form included validation of the structural model using molecular dynamics simulation, comparison of the dynamics of the 7TM and 6TM variants, and comparison of morphine dynamics in the binding pockets of the 7TM and 6TM variants.
  • the 6TM form of the human mu opioid receptor is due to a splice variant containing exon 13 with a translation start at exon 2.
  • This 6TM variant is missing the first transmembrane helix HI in the canonical 7-transmembrane helix topology of G-protein coupled receptors (GPCRs).
  • GPCRs G-protein coupled receptors
  • FIG. 9 shows the 6TM variant molecular dynamics simulation.
  • the 6TM structure simulation used explicit models for the protein (shown embedded in the bilayer), morphine, lipids (shown as sticks), ions (spheres), and water (not shown).
  • RMSD root mean square deviation
  • FIG. 11 shows the superposition of the human mu opioid receptor 6TM variant conformation before simulation (in cyan color) and after simulation (in green color).
  • FIG. 12 shows a corresponding superposition view from the extracellular side of the superposition of the human mu opioid receptor 6TM variant conformation before simulation (in cyan color) and after simulation (in green color). Side chains shown in sticks are within 4 A of the bound morphine.
  • FIGS. 13-16 show the effect of ligand on human mu opioid receptor flexibility. Simulations of the 7TM and 6TM variants with and without ligands were performed.
  • FIG. 13 is a plot of the root mean square fluctuations (RMSF), in Angstroms, for each residue during the simulation of the 7TM variant with and without morphine.
  • FIG. 14 is a depiction of the 7TM variant with and without morphine, with the RMSF values mapped onto the protein structure.
  • FIG. 15 is a plot of the root mean square fluctuations (RMSF), in Angstroms, for each residue during the simulation of the 6TM variant with and without morphine.
  • FIG. 16 is a depiction of the 6TM variant with and without morphine, with the RMSF values mapped onto the protein structure. The backbone thickness and color are proportional to the RMSF values. Arrows indicate the regions that change flexibility in the presence of morphine.
  • FIG. 17 shows the binding pocket residues with their calculated contact frequencies for the 7TM variant (left panel) and the 6TM variant (right panel), together with a contact probability scale shown at the far right for the 7TM and 6TM panels. Residues within the 4.5 A of the bound morphine are illustrated. Side-chains are colored according to their contact probability, which is defined as the likelihood of interacting with morphine during the simulation run. A contact probability of 1 indicates that the specific residue is always within 4.5 A of morphine, while a contact probability of 0 indicates that the residue is always beyond 4.5 A of morphine.
  • FIG. 18 shows residues specific to both 6TM and 7TM variant binding pockets. Mutations in these sites affect ligand binding to both variants. Nonetheless, some other sites are specific only to one of such forms. For example, mutations in these sites, e.g., to alanine, adversely affect ligand binding in one form more than the other.
  • FIG. 19 shows mutation sites that affect binding to the 7TM variant more than to the 6TM variant.
  • FIG. 20 shows mutation sites that affect binding to the 6TM variant more than to the 7TM variant.
  • the two compound libraries include a lead-like library that contains 1,296,388 compounds, and a drug-like focused library containing 55,227 compounds.
  • Each compound was compositionally docked onto the human mu opioid receptor structures and its binding affinity was estimated based on the docking poses. For the large-scale docking, only one representative conformation for both 7TM and 6TM human mu opioid receptor was used, which was selected as the centroid structure of the largest clusters during the equilibrium MD simulation.
  • FIG. 21 is a schematic flow chart for the virtual screening process for identifying binding ligands to a protein target, as utilized to identify modulator compounds for 7TM and 6TM human mu opioid receptor variants.
  • Table 3 lists some known mu opioid receptor drugs and their binding score for 7TM and 6TM mu opioid receptor.
  • Table 4 below lists the top 100 compounds from the lead-like library that have the highest predicted binding energy for 7TM mu opioid receptor.
  • Table 5 lists the top 100 compounds from the lead-like library that have the highest predicted binding energy for 6TM mu opioid receptor. [00216] Table 5
  • Table 6 below lists the top 10 compounds from the lead-like library that have the highest predicted binding energy for 6TM and 7TM mu opioid receptor.
  • nalmefene an opioid receptor antagonist
  • any of the foregoing compounds exhibiting mu opioid receptor binding affinity and therapeutic or diagnostic effect can be utilized in compositions and formulations of the invention, and in the methods and techniques herein disclosed.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur une composition pharmaceutique comprenant (i) un composé modulant le récepteur des opioïdes de type mu choisi dans le groupe constitué par les composés du groupe I, les composés apparentés et leurs dérivés pharmaceutiquement acceptables, (ii) un véhicule pharmaceutiquement acceptable et (iii) éventuellement, un autre agent thérapeutique. L'invention porte également sur des méthodes thérapeutiques d'administration de composés modulant le récepteur des opioïdes de type mu et sur des formulations cocktails avec d'autres composés se fixant au récepteur des opioïdes de type mu, par exemple la morphine, la (+)-morphine, la méthadone, la (+)-méthadone, la 3-méthoxynaltrexone, l'étorphine ou la naltrexone.
PCT/US2012/040168 2011-05-31 2012-05-31 Composés se fixant au récepteur des opioïdes de type mu Ceased WO2012166891A2 (fr)

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US201161491828P 2011-05-31 2011-05-31
US61/491,828 2011-05-31

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Cited By (5)

* Cited by examiner, † Cited by third party
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WO2017200970A1 (fr) * 2016-05-19 2017-11-23 Virginia Commonwealth University Modulateurs puissants et sélectifs des récepteurs opioïdes mu
WO2021007366A1 (fr) * 2019-07-08 2021-01-14 St. Louis College Of Pharmacy Agonistes/analgésiques au récepteur opioïde à polarisation de protéine g à recrutement d'arrestine réduit
US10934291B2 (en) 2014-09-25 2021-03-02 Duke University Kinase inhibitors and related methods of use
JP2021510707A (ja) * 2018-01-15 2021-04-30 ユーシービー バイオファルマ エスアールエル Ｉｌ−１７モジュレータとしての縮合イミダゾール誘導体
WO2022182395A1 (fr) * 2021-02-26 2022-09-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs à petites molécules de domaine n-terminal de stat3 et méthodes d'utilisation

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US20040048874A1 (en) * 2001-05-22 2004-03-11 Bardsley Hazel Judith New therapeutic use of 4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D]pyrimidine
BRPI0719305A2 (pt) * 2006-11-22 2014-02-04 Progenics Pharm Inc (r)-n-estereoisômeros de análogos de 7,8-saturados-4,5-epóxi-morfinano

Cited By (9)

* Cited by examiner, † Cited by third party
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US10934291B2 (en) 2014-09-25 2021-03-02 Duke University Kinase inhibitors and related methods of use
US11999737B2 (en) 2014-09-25 2024-06-04 Duke University Kinase inhibitors and related methods of use
WO2017200970A1 (fr) * 2016-05-19 2017-11-23 Virginia Commonwealth University Modulateurs puissants et sélectifs des récepteurs opioïdes mu
US10988481B2 (en) 2016-05-19 2021-04-27 Virginia Commonwealth University Potent and selective mu opioid receptor modulators
JP2021510707A (ja) * 2018-01-15 2021-04-30 ユーシービー バイオファルマ エスアールエル Ｉｌ−１７モジュレータとしての縮合イミダゾール誘導体
US11472794B2 (en) * 2018-01-15 2022-10-18 UCB Biopharma SRL Fused imidazole derivatives as IL-17 modulators
WO2021007366A1 (fr) * 2019-07-08 2021-01-14 St. Louis College Of Pharmacy Agonistes/analgésiques au récepteur opioïde à polarisation de protéine g à recrutement d'arrestine réduit
US11613547B2 (en) 2019-07-08 2023-03-28 University Of Health Sciences & Pharmacy In St. Louis G-protein biased opioid receptor agonist/analgesics with reduced arrestin recruitment
WO2022182395A1 (fr) * 2021-02-26 2022-09-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs à petites molécules de domaine n-terminal de stat3 et méthodes d'utilisation

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