title: Synthesis and biological evaluation of alpha- and beta-6-amido derivatives of 17-cyclopropylmethyl-3, 14beta-dihydroxy-4, 5alpha-epoxymorphinan: potential alcohol-cessation agents.
abstract: Substituted aryl and aliphatic amide analogues of 6-naltrexamine were synthesized and used to characterize the binding to and functional activity of human mu-, delta-, and kappa-opioid receptors. Competition binding assays showed 11-25 and 27-31 bound to the mu (K(i) = 0.05-1.2 nM) and kappa (K(i) = 0.06-2.4 nM) opioid receptors. Compounds 11-18 possessed significant binding affinity for the delta receptor (K(i) = 0.8-12.4 nM). Functional assays showed several compounds acted as partial or full agonists of delta or kappa receptors while retaining an antagonist profile at the mu receptor. Structure-activity relationship for aryl amides showed that potent compounds possessed lipophilic groups or substituents capable of hydrogen bonding. Metabolic stability studies showed that 11, 12, and 14 possessed considerable stability in the presence of rat, mouse, or human liver preparations. The ED 50 of inhibition of 10% ethanol self-administration in trained rats, using operant techniques for 11, was 0.5 mg/kg.
authors.affiliation: Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA.
authors.forename: Senait
authors.initials: S
authors.lastname: Ghirmai
authors.forename: Marc R
authors.initials: MR
authors.lastname: Azar
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Polgar
authors.forename: Ilona
authors.initials: I
authors.lastname: Berzetei-Gurske
authors.forename: John R
authors.initials: JR
authors.lastname: Cashman
mesh_terms: D000428:Alcohol Drinking; D000437:Alcoholism / Q000188:drug therapy*; D000577:Amides / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D004353:Drug Evaluation, Preclinical; D000431:Ethanol / Q000008:administration & dosage; D006801:Humans; D006860:Hydrogen Bonding; D008099:Liver / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000627:therapeutic use; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D000431:Ethanol; D009271:Naltrexone