(E)- and (Z)-7-arylidenenaltrexones: Synthesis and opioid receptor radioligand displacement assays

Abstract

The E-isomer of 7-benzylidenenaltrexone (BNTX, 1a) was reported by Portoghese as a highly selective δ-opioid antagonist. The corresponding Z- isomer 1b was not readily available through direct aldol condensation of naltrexone (6) with benzaldehyde. Using the photochemical methods employed by Lewis to isomerize cinnamamides, we have obtained Z-isomer 1b in good yield from E-isomer 1a. A series of (E)- and (Z)-7-arylidenenaltrexone derivatives was prepared to study the effect of larger arylidene groups on opioid receptor affinity in this series. By aldol condensation of naltrexone (6) with benzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, 4-phenylbenzaldehyde, and 9-anthracaldehyde, the (E)-arylidenes were readily obtained. Photochemical isomerization afforded the corresponding Z-isomers. These compounds were evaluated via opioid receptor radioligand displacement assays. In these assays, the Z-isomers generally had higher affinity and were more D- selective than the corresponding E-isomers. The (Z)-7-(1- naphthylidene)naltrexone (3b) showed the greatest selectivity (δ:μ ratio of 15) and highest affinity δ-binding (K(i) = 0.7 nM). PM3 semiempirical geometry optimizations suggest a significant role for the orientation of the arylidene substituent in the binding affinity and δ-receptor selectivity. This work demonstrates that larger groups may be incorporated into the arylidene portion of the molecule with opioid receptor affinity being retained.