Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 11. 3-Hydroxycyprodime and Analogs: Opioid Antagonist Profile in Comparison to Cyprodime

• Published in: Journal of medicinal chemistry Vol. 38; no. 16; pp. 3071 - 3077
• Main Authors: Schmidhammer, Helmut, Jennewein, Herwig K, Krassnig, Roland, Traynor, John R, Patel, Dinesh, Bell, Katrina, Froschauer, Gudrun, Mattersberger, Karin, Jachs-Ewinger, Christine
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.08.1995; Amer Chemical Soc
• Subjects: Animals; Brain - drug effects; Chemistry, Medicinal; Guinea Pigs; Ileum - drug effects; In Vitro Techniques; Life Sciences & Biomedicine; Male; Morphinans - chemical synthesis; Morphinans - chemistry; Morphinans - pharmacology; Muscles - drug effects; Myenteric Plexus - drug effects; Narcotic Antagonists - chemistry; Narcotic Antagonists - pharmacology; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Vas Deferens - drug effects; SUBTYPES; DELTA; MOUSE; ISOLATED VAS-DEFERENS; RAT-BRAIN; HIGHLY POTENT; BINDING-SITES; SELECTIVITY; RECEPTOR ANTAGONIST; MESSAGE ADDRESS CONCEPT
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00016a010

A series of 3-hydroxy-substituted analogues (3-7) of the mu selective opioid antagonist cyprodime has been synthesized in order to evaluate the role of a hydroxy group at C-3 concerning mu opioid antagonist selectivity. Compounds 3-7 were tested in bioassays (electrical stimulated mouse vas deferens preparation and myenteric-plexus longitudinal muscle preparation of the guinea pig ileum) and opioid receptor binding assays. Antagonism of mu receptor-mediated responses induced by the mu selective agonist DAMGO afforded equilibrium dissociation constants in the mouse vas deferens preparation (K-e values) for compounds 3-7 which agreed closely with their affinities as determined by opioid receptor binding assays (K-i values). At kappa and delta receptors differences were apparent. Although the compounds had high affinity for both kappa and delta receptors in opioid receptor binding, they were very poor at antagonizing agonist responses mediated by kappa and particularly delta agonists in the mouse vas deferens preparation. None of the compounds tested showed agonist potency in the mouse vas deferens preparation or the myenteric-plexus longitudinal muscle preparation of the guinea pig ileum.