CHARACTERIZATION OF 9 SLOWLY DISSOCIATED OPIOID LIGANDS AZABICYCLONONANES COMPOUNDS TO MU, DELTA, AND KAPPA RECEPTORS

In the receptor binding assay, the relative affinity ratios of P-7548 [3-(beta-phenylethyl)-9-beta-methoxy-9-alpha-(m-propionoxyphenyl)-3-azabicyclo (3,3,1)nonane], P-7556 [3-(beta-phenylethyl)-9-beta-methoxy-9-alpha-(m-benzoyloxyphenyl)-3-azabicyclo(3,3,1)nonane] and P-7618 {3-(beta-phenylethyl)-9-beta-methoxy-9-alpha-[m-(l-cyclopentyl-propionoxyphenyl)]-3-azabicyclo(3,3,1) nonane} were 56:16:1, 1:4:1, and 6:0.2:1 at mu, delta, and kappa-sites, respectively. These compounds possessed a tight binding to mu-receptor. After washed 4 times, they still inhibited the [H-3]ohmefentanyl binding by 70-80%. In the guinea pig ileum, they showed potent and persistent agonist activities, 607, 303, and 181 times respectively that of normorphine. These effects were readily antagonized by naloxone and Mr2266. In the mouse vas deferens (MVD), they also possessed long-lasting agonist activities. The effect of P-7556 on MVD was not antagonized by naloxone and Mr2266, indicating that P-7556 acted on delta-receptor in MVD. In the rabbit vas deferens, P-7548, P-7556, and P-7618 antagonized the effect of U-50488H. We conclude that these azabicyclononanes are a series of opioid ligands with mu, delta-agonist and kappa-antagonist activities.