Synthesis and delta-opioid receptor antagonist activity of a naltrindole analogue 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 dihydropseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorphinan 2 was found to be approximately 1/60th as potent as naltrindole 1 in the MVD and an agonist in the GPI preparation. A comparable difference 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 subsite on the delta receptor is critical for potent delta antagonist activity.