Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a µ-agonist δ-antagonist and δ-inverse agonists

Abstract

Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl moiety on the nitrogen atom, were synthesized and their binding affinity to the µ-, δ-, and κ-opioid receptors was examined. The higher affinity ligands were further examined in the [³⁵S]GTPγS assay to study their function and efficacy. 3-((1R,5S)-(−)-2-(4-Nitrophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((−)-10m) was found to be a µ-agonist and δ-antagonist in that functional assay and was about 50 fold more potent than morphine in vivo. 3-((1R,5S)-(−)-2-(4-Chlorophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((−)-10i) and several other ligands displayed inverse agonist activity at the δ-opioid receptor. The absolute configuration of all of the reported compounds was established by chemical conversion of (−)-6 to 1R,5S-(−)-8b·HBr.