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

P. S. Portoghese, C. E. Lin, F. Farouz-Grant, A. E. Takemori

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1495-1500
Number of pages6
JournalJournal of medicinal chemistry
Volume37
Issue number10
DOIs
StatePublished - May 1 1994

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