Agonist and antagonist opioid activity of axial and equatorial conformations of S-methyl- and S-allyl-morphinans

Resolved axial (β) and equatorial (α) forms of S-methyl (β-sulforphanol, α-sulforphanol) and S-allyl (β-sulfallorphan, α-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 μ-, δ-, and κ-opioid receptors in membrane preparations of rat brain and guinea pig cerebellum and to produce analgesia in a rat thermal pain assay. β-Sulforphanol was more potent than α-sulforphanol in the guinea pig ileum (relative potencies of 93% and 29% respectively, as compared with levorphanol). β-Sulfallorphan were both inactive in the guinea pig ileum assay. In the mouse vas deferens preparation, β-sulforphanol and α-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 μ-opioid receptors but α-sulfallorphan also showed significant binding potency on δ-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, α-sulfallorphan potently inhibited morphine with a K e value of 41.7 nM. α-Sulforphanol also antagonized morphine but with a smaller potency ( K e = 350 nM). In the mouse vas deferens, no antagonist activity against morphine was observed with any morphinan derivative tested at 1 μM. In the rat thermal pain assay, β-sulforphanol (intracisternally, i.c.) was more potent than α-sulforphanol in producing analgesia while the other morphinan derivatives were inactive. In addition, α-sulfallorphan displayed potent antagonist activity against the antinoceceptive effect of levorphanol and in this respect it was at least 10 times as potent as β-sulfallorphan. These data indicate that the equatorial conformation of the allyl group in morphinan derivatives confers an antagonist property to the molecule while the agonist activity of sulforphanol greatly depends upon the axial orientation of the methyl group.