SYNTHESIS AND KAPPA-OPIOID ANTAGONIST SELECTIVITY OF A NORBINALTORPHIMINE CONGENER - IDENTIFICATION OF THE ADDRESS MOIETY REQUIRED FOR KAPPA-ANTAGONIST ACTIVITY

Compound 2, which represents a structurally simplified congener of norbinaltorphimine 1a, was synthesized in order to evaluate the role of its second basic nitrogen-in conferring kappa-opioid receptor antagonist selectivity. Congener 2 was found to beat least twice as selective as 1a as a kappa antagonist, while its N-carbobenzoxy derivative (3) was inactive at kappa-receptors. This study establishes the importance of the second basic nitrogen of 1a for kappa-receptor recognition. It is proposed that this basic group.mimics the guanidinium moiety of Arg7, which may be the key kappa-address component of dynorphin.