Probes for narcotic receptor mediated phenomena. Part 42: Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans

Abstract

A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan( rac-(3 R,6a S,11a S)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1 H-3,6a-methanobenzofuro[2,3- c]azocin-10-ol ( 12)) was found to have the highest μ-opioid receptor affinity ( K i = 1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([ 35S]GTP-γ-S) showed that the racemate 12 was more than three times more potent than naloxone as an μ-opioid antagonist.