STRUCTURE-ACTIVITY RELATIONSHIP OF N17'-SUBSTITUTED NORBINALTORPHIMINE CONGENERS - ROLE OF THE N17' BASIC GROUP IN THE INTERACTION WITH A PUTATIVE ADDRESS SUBSITE ON THE KAPPA-OPIOID RECEPTOR

A series of norbinaltorphimine congeners (2-12) which contain different groups at the N17'-position have been synthesized in order to evaluate the role of N17' in conferring kappa opioid antagonist selectivity at opioid receptor sites. The compounds that contain a basic N17' nitrogen (2-9) were found to be selective kappa antagonists. Amidation of N17' afforded congeners 10-12 with feeble kappa antagonist potency and low selectivity. The fact that potent antagonism and selectivity were observed only when members of the series contain a basic N17' nitrogen suggests that it interacts with extracellular domains of the kappa receptor that contain acidic amino acid residues. The N-terminal domain and extracellular loop 2, both of which contain acidic residues, are candidates for this interaction and may be components of the kappa address subsite of the receptor.