title: Agonist and antagonist opioid activity of axial and equatorial conformations of S-methyl- and S-allyl-morphinans.
abstract: Resolved axial (beta) and equatorial (alpha) forms of S-methyl (beta-sulforphanol, alpha-sulforphanol) and S-allyl (beta-sulfallorphan, alpha-sulfallorphan) morphinans were tested for their ability to depress the electrically evoked contractions of the guinea pig ileum and of the mouse vas deferens, to compete with the binding of prototype ligands selective for mu-, delta-, and kappa-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum and to produce analgesia in a rat thermal pain assay. beta-Sulforphanol was more potent than alpha-sulforphanol in the guinea pig ileum (relative potencies of 93% and 29% respectively, as compared with levorphanol). beta-Sulfallorphan and alpha-sulfallorphan were both inactive in the guinea pig ileum assay. In the mouse vas deferens preparation, beta-sulforphanol and alpha-sulforphanol had relative potencies of 2.1% and 1.2% as compared with levorphanol, respectively, while the S-allyl derivatives were inactive. All morphinan derivatives displayed marked binding selectivity for mu-opioid receptors but alpha-sulfallorphan also showed significant binding potency on delta-opioid receptors (12% as compared to levorphanol). The compounds were also tested for their ability to antagonize the biological activity of morphine. In the guinea pig ileum, alpha-sulfallorphan potently inhibited morphine with a Ke value of 41.7 nM. alpha-Sulforphanol also antagonized morphine but with a smaller potency (Ke = 350 nM). In the mouse vas deferens, no antagonist activity against morphine was observed with any morphinan derivative tested at 1 microM. In the rat thermal pain assay, beta-sulforphanol (intracisternally, i.c.) was more potent than alpha-sulforphanol in producing analgesia while the other morphinan derivatives were inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Lemaire
authors.forename: B
authors.initials: B
authors.lastname: Belleau
authors.forename: F B
authors.initials: FB
authors.lastname: Jolicoeur
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009019:Morphinans / Q000737:chemistry / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010147:Pain Measurement; D011869:Radioligand Assay; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D009019:Morphinans; D011957:Receptors, Opioid