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 synthetized in order to evaluate the role of is second basic nitrogen in conferring k-opioid receptor antagonist selectivity. Congener 2 was found to be at least twice as selective as 1a as a k antagonist, while is N-carbobenzoxy derivative (3) was inactive at k-receptors. This study establishes the importance of the second basic nitrogen of 1a for k-receptor recognition. It is proposed that this basic group mimics the guanidinium moiety of Arg 7 , which may be the key k-address component of dynorphin