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

In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-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 7α-amino (5a), 7α-alkylamino (5b–e), or 7α-dialkylamino (5f–h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties