SYNTHESIS AND DELTA-OPIOID RECEPTOR ANTAGONIST ACTIVITY OF A NALTRINDOLE ANALOG WITH A REGIOISOMERIC INDOLE MOIETY

Indolomorphinans 2 and 3, in which the indole moiety is fused to the 7 ,8-position of the morphinan system, have been synthesized from dihydr opseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorp hinan 2 was found to be similar to 1/60th as potent as naltrindole 1 i n the MVD and an agonist in the GPI preparation. A comparable differen ce in affinity between 1 and 2 was observed. The methyl analogue 3 was inactive in both preparations. The results of this study support the idea that the regio orientation of the indolic benzene moiety of 1 is optimal for delta-opioid receptor antagonist activity. It is proposed that the proper alignment of the benzene moiety with an address subsit e on the delta receptor is critical for potent delta antagonist activi ty.