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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Medicinal Chemistry|
|State||Published - May 10 1996|
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery