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J Med Chem. 1994 May 13;37(10):1495-500.

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.

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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.


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.

[Indexed for MEDLINE]

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