Probes for narcotic receptor-mediated phenomena. 21. Novel derivatives of 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl) phenols with improved δ opioid receptor selectivity

Derivatives of racemic and optically pure levorotatory 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl) phenols containing methoxy substituents in the C10′, C9′, and C8′ positions (compounds 9-11, respectively) were synthesized and characterized by spectroscopic and X-ray methods. The binding affinities for the μ, δ, and κ₁ opioid receptors and activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD) functional bioassays were determined for these compounds. A methoxy substituent in the C8′ position decreases the binding affinity for both the μ and δ receptors, while a C10′ methoxy substituent has little effect on either binding affinity. Interestingly, a methoxy group at the C9′ position in the levorotatory series provides compound (-)-10 which exhibits both enhanced in vitro affinity and selectivity for the δ opioid receptor relative to the unsubstituted derivative (-)-8 and is the most selective (μ/δ IC₅₀ ratio 17.9, κ₁/δ IC₅₀ ratio 314) and highest affinity (IC₅₀ 3.7 nM) δ receptor ligand for this novel class of compounds. The results of the GPI and MVD bioassays are more dramatic and indicate that (-)-10 is an agonist for the δ receptor (IC₅₀ 49.0 nM) with substantial selectivity for the δ versus the μ receptor borne out by a GPI/MVD IC₅₀ ratio of >612.