4beta-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4beta-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist

Abstract

In previous studies we reported that addition of 7alpha-acylamino groups to N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7alpha-amino (5a), 7alpha-alkylamino (5b-e), or 7alpha-dialkylamino (5f-h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7alpha-amino and 7alpha-methylamino analogues were full agonists at the mu and delta receptors and antagonists at the kappa receptor. The 7alpha-cyclopropylmethylamino analogue 5h was a full agonist at the mu receptor with weaker agonist activity at the delta and kappa receptors. Whereas the addition of a 7alpha-acylamino group to the pure nonselective opioid receptor antagonist N-phenylpropyl-4beta-methyl-5-(3-hydroxyphenyl)morphan (4) led to kappa selective pure opioid receptor antagonist, the addition of a 7alpha-amino, 7alpha-alkylamino, or 7alpha-dialkylamino group to 4 leads to opioid ligands that are largely mu or delta agonist with mixed agonist/antagonist properties