Synthesis and biological activity of 8β-substituted hydrocodone indole and hydromorphone indole derivatives

The 8β-unsubstituted and substituted analogues of hydrocodone indole and hydromorphone indole were synthesized and their binding affinities to opioid receptors were determined. Introduction of an 8β-methyl group into the indolomorphinan nucleus increased affinity at all opioid receptors. 6,7-Dehydro-4,5α-epoxy-8β-methyl-6,7,2′,3′-indolomorphinan (9) was found to be a δ antagonist with subnanomolar affinity (0.7 nM) for the δ-opioid receptor, and to have good δ-selectivity (μ/δ=322).