Electrophilic N-Benzylnaltrindoles as δ Opioid Receptor-Selective Antagonists

Vijaya L. Korlipara, Akira E. Takemori, Philip S. Portoghese

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The N-benzyl group of N-benzylnaltrindole (1, BNTI), a potent and selective δ2 opioid receptor antagonist, was employed as a scaffold to hold electrophilic moieties (isothiocyanate and haloacetamide) in an effort to obtain selective affinity labels (2-4 and 8-11). The corresponding acetamide derivatives (5-7) also were synthesized to serve as nonelectrophilic controls. The o- and p-isothiocyanates (2 and 4) and the haloamides (8-11) were selective δ opioid receptor antagonists in the mouse vas deferens (MVD) preparations, while the meta isomer 3 was a δ-selective full agonist (IC50 = 5 nM). The fact that the effect of 2 and 4 was found to increase as a function of time in MVD suggests a covalent mechanism for the wash resistant component. The m-isothiocyanate 3 was found to be a ó-selective and irreversible agonist in the MVD, and it is suggested that it may be covalently binding to an agonist recognition site. In the mouse abdominal stretch antinociceptive assay, compounds 2-4 and 9 were δ-selective antagonists but exhibited δ21 selectivity ratios lower than that of BNTI.

Original languageEnglish (US)
Pages (from-to)1337-1343
Number of pages7
JournalJournal of medicinal chemistry
Issue number8
StatePublished - Apr 1 1995


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