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US 2014/0371255 A1Published application
Non-peptidyl, potent, and selective mu opioid receptor antagonists and their use in treating opioid addiction and opioid induced constipation
AssigneeVirginia Commonwealth University
InventorsYan Zhang, Dana E. Selley, William Dewey
Life of this patent
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Abstract
Selective, non-peptide antagonists of the mu opioid receptor (MOR) and methods of their use are provided. The antagonists may be used, for example, to identify MOR agonists in competitive binding assays, and to treat conditions related to addiction in which MOR is involved, e.g. heroin, prescription drug and alcohol addiction, as well as in the treatment of opioid induced constipation (OIC).
Claims15
A selective, non-peptide MOR antagonist of the general formula
- wherein
- the MOR antagonist may be a racemic mixture or a purified racemate;
- the nitrogen (N) at the 17N position may be charged and substituted with a C1-10 aryl or alkaryl, or may be uncharged and unsubstituted;
- Z is selected from the group consisting of a substituted or unsubstituted aliphatic moiety;
- NH;
- CO;
- (NHCO)n where n=1-5;
- (CONH)n where n=1-5;
- (NHCO)(CH2)n(NHCO), where n=1-5;
- (NHCO)(CH2)n where n=1-5;
- (CH2)n(NHCO), where n=1-5;
- and O;
- R is selected from the group consisting of substituted and unsubstituted heteroaromatic rings including without limitation
- wherein any carbon of said heteroaromatic ring may be bonded to a hydrogen or be substituted with a substitution selected from the group consisting of substituted or unsubstituted C1-5 alkyl, C1-5 alyleether, carboxylic acid, nitrogen, cyano, nitro, halogen, or amino moiety, and where the substitution may be the same or different when more than one carbon is substituted,
- wherein the nitrogen in the heteroarmatic ring may be charged and substituted with a C-10 alkyl or alkaryl, or be uncharged and unsubstituted;
- and
- wherein in addition to the nitrogen substitution in said heteroaromatic ring, one or more carbons within said heteroaromatic ring may be replaced by a substitution with a ring selected from the group consisting of N, S, P, and O.
14 more elements
A method of testing whether or not a candidate compound is a MOR angonist, comprising the step of
- conducting competitive inhibition tests between said candidate compound and a MOR antagonist selected from the group consisting of:
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(2′-chloropyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(2′-bromopyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(2′-cyanopyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(2′-methylpyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(2′-methoxypyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(3′-chloropyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(3′-bromopyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(3′-methylpyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5-epoxy-6β-{[4′-(3′-methoxylpyridyl)]carboxamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[2′-(pyridine-4″-yl)acetamido]morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[3′-(pyridine-4″-yl)propanamido]morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{2′-[(pyridine-4″-yl)carboxamido]acetamido})morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(2′-pyridazine) carboxamido]morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(2′-pyrimidine) carboxamido]morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(1′-methylpiperidine-4′-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[2-(isoquinolin-3-yl)acetamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[3-(isoquinolin-3-yl)propanamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[2-(isoquinoline-3-carboxamido)acetamido}morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(1-chloro-4-methoxyisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(1-chloro-4-hydroxyisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(4-hydroxyisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(4-quinazoline-2-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(1-chloroisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(1-cyanoisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(1-methylisoquinolin-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(6-nitroisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(7-nitroisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(7-dimethylaminoisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(6,7-dimethoxyisoquinoline-3-carboxamido)morphinan;
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(S)-(2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)]morphinan;
- and
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(7-dimethylamino-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)morphinan.
30 more elements
A method of treating symptoms of addiction related to MOR in a patient in need thereof, comprising
- administering to said patient a MOR antagonist of general formula
- wherein
- the MOR antagonist may be a racemic mixture or a purified racemate;
- the nitrogen (N) at the 17N position may be charged and substituted with a C1-10 alkyl or alkaryl, or may be uncharged and unsubstituted;
- Z is selected from the group consisting of a substituted or unsubstituted aliphatic moiety;
- NH;
- CO;
- (NHCO)n where n=1-5;
- (CONH)n where n=1-5;
- (NHCO)(CH2)n(NHCO), where n=1-5;
- (NHCO)(CH2)n where n=1-5;
- (CH2)n(NHCO), where n=1-5;
- and O;
- R is selected from the group consisting of substituted and unsubstituted heteroaromatic rings including without limitation
- wherein any carbon of said heteroaromatic ring may be bonded to a hydrogen or be substituted with a substitution selected from the group consisting of substituted or unsubstituted C1-5 alkyl, C1-5 alyleether, carboxylic acid, nitrogen, cyano, nitro, halogen, or amino moiety, and where the substitution may be the same or different when more than one carbon is substituted,
- wherein the nitrogen in the heteroarmatic ring may be charged and substituted with a C-10 alkyl or alkaryl, or be uncharged and unsubstituted;
- and
- wherein in addition to the nitrogen substitution in said heteroaromatic ring, one or more carbons within said heteroaromatic ring may be replaced by a substitution with a ring selected from the group consisting of N, S, P, and O.
15 more elements
A method of treating symptoms opioid induced constipation in a patient in need thereof, comprising
- administering to said patient a MOR antagonist of general formula
- wherein
- the MOR antagonist may be a racemic mixture or a purified racemate;
- the nitrogen (N) at the 17N position may be charged and substituted with a C1-10 alkyl or alkaryl, or may be uncharged and unsubstituted;
- Z is selected from the group consisting of a substituted or unsubstituted aliphatic moiety;
- NH;
- CO;
- (NHCO)n where n=1-5;
- (CONH)n where n=1-5;
- (NHCO)(CH2)n(NHCO), where n=1-5;
- (NHCO)(CH2)n where n=1-5;
- (CH2)n(NHCO), where n=1-5;
- and O;
- R is selected from the group consisting of substituted and unsubstituted heteroaromatic
- wherein any carbon of said heteroaromatic ring may be bonded to a hydrogen or be substituted with a substitution selected from the group consisting of substituted or unsubstituted C1-5 alkyl, C1-5 alyleether, carboxylic acid, nitrogen, cyano, nitro, halogen, or amino moiety, and where the substitution may be the same or different when more than one carbon is substituted,
- wherein the nitrogen in the heteroarmatic ring may be charged and substituted with a C-10 alkyl or alkaryl, or be uncharged and unsubstituted;
- and
- wherein in addition to the nitrogen substitution in said heteroaromatic ring, one or more carbons within said heteroaromatic ring may be replaced by a substitution with a ring selected from the group consisting of N, S, P, and O.
15 more elements
Dependencies are inferred from the claim text.