Synthesis and SAR Study of Opioid Receptor Ligands: Mono‐ and Bis‐Indolomorphinans

Abstract

Mono- and bis-indolomorphinans were synthesized through a multi-step synthetic approach from the alkaloid, thebaine, to further explore the C-ring SAR (structure-activity relationship) of morphinan scaffold. Both mono-indoles displayed good binding affinity and selectivity for the delta receptor, with compound 6b possessed the highest K(i) value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both delta and kappa receptors, but moderate binding at the mu receptor was observed. Functional assays indicated that the newly synthesized mono-indole 6b was delta-agonist, opposite to the delta-antagonist profile of naltrindole. Bisindoles 7a,b were mu-agonists. This work further confirms that the phenol component in opioids is essential for higher binding to the opioid receptors. The different binding ability, receptor selectivity, and the functional activity profiles of naltrindole 2, monoindole 6b, and bisindole 7b clearly indicated that they interact with the opioid receptors in different modes.