delta opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole

To investigate the effect of the introduction of a 4-phenolic substituent o n the delta opioid affinity and selectivity of the indolomorphinans, a rang e of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (mu, kappa, delta), 17-cyclopropylmethyl-6,7 -didehydro-4-hydroxy-3-methoxy-6,7:2',3'-indolomorphinan (13) was an except ion, displaying excellent delta binding selectivity (delta K-i = 7 nM, mu/d elta = 1900, mu/kappa = 1130). GTP-gamma-S functional assays showed 13 to b e a selective delta antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomo rphinans that are known to reduce mu activity, to obtain increased delta se lectivity.