beta-funaltrexamine and beta-naltrexamine

Cinnamoyl derivatives of beta-naltrexamine (beta-NTA) have been prepared and evaluated as potential irreversible opioid antagonists. In receptor binding assays, isolated tissue preparations and mouse antinociception assays the p-methylcinnamoyl derivative BU42 was similar to the standard opioid ligand beta-funaltrexamine (beta-FNA). The main features were reversible kappa agonism and irreversible mu antagonism. Surprisingly the p-chlorocinnamoyl derivative BU59 showed only modest competitive antagonist activity in-vivo despite appearing to bind irreversibly to mu receptors in the guinea-pig ileum (GPI) preparation. BU60, the dihydrocinnamoyl analogue of BU59, like BU59 displayed reversible kappa agonism in GPI but in mouse antinociception assays its agonism was mediated by mu and delta receptors rather than kappa. The surprising changes of profile attributable to substitution in the aromatic ring of the cinnamoylamido group in this small series suggests that a larger range of substituted cinnamoylamido derivatives should be studied to further elucidate the effects of Michael acceptor activity and other factors.

Topics: Animals; Dose-Response Relationship, Drug; Guinea Pigs; Ileum; Male; Mice; Naltrexone; Narcotic Antagonists; Pain Measurement; Receptors, Opioid; Vas Deferens