Potential irreversible ligands for opioid receptors. Cinnamoyl derivatives of β-naltrexamine

Cinnamoyl derivatives of β-naltrexamine (β-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 β-funaltrexamine (β-FNA). The main features were reversible κ agonism and irreversible μ antagonism. Surprisingly the p-chlorocinnamoyl derivative BU59 showed only modest competitive antagonist activity in-vivo despite appearing to bind irreversibly to μ receptors in the guinea-pig ileum (GPI) preparation. BU60, the dihydrocinnamoyl analogue of BU59, like BU59 displayed reversible κ agonism in GPI but in mouse antinociception assays its agonism was mediated by μ and δ receptors rather than κ. 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.