Structure-Activity Relationship of N17′-Substituted Norbinaltorphimine Congeners. Role of the N17′ Basic Group in the Interaction with a Putative Address Subsite on the κ 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 k opioid antagonist selectivity at opioid receptor sites. The compounds that contain a basic N17′ nitrogen (2–9) were found to be selective k antagonists. Amidation of N17′ afforded congeners 10–12 with feeble k 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 k 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 k address subsite of the receptor.