4β-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4β-methyl-5-(3-hydroxyphenyl)morphan pure antagonist

Abstract

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 nonselective 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.

Scheme 1^a

^aReagents: (a) Formic acid, PyBOP, DIPEA, CH₂Cl₂; (b) LAH, THF; (c) R₁CHO, NaBH₃(CN), CF₃CH₂OH; (d) Paraformaldehyde, NaBH₃(CN), CF₃CH₂OH

Scheme 2^a

^aReagents: (a) Zn, HCl; (b) ACE-Cl, DCE, reflux; (c) MeOH, reflux; (d) 3-phenylpropionaldehyde, NaBH₃(CN), CF₃CH₂OH; (e) BBr₃, CH₂Cl₂