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.
Portoghese
P S
PS
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Lin
C E
CE
Farouz-Grant
F
F
Takemori
A E
AE
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone