Role of Spacer and Address Components in Peptidomimetic δ Opioid Receptor Antagonists Related to Naltrindole

P. S. Portoghese, H. Nagase, K. E. MaloneyHuss, C. E. Lin, A. E. Takemori

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Abstract

A series of heterocyclic analogues 2-5 related to naltrindole (1) (NTI) and 6-arylnaltrexone derivatives 6-8 were synthesized in order to determine the role of the spacer and the address moieties in conferring i opioid receptor antagonist activity. The benzofuran (NTB), quinoxaline, and quinoline analogues (2, 3, and 4, respectively) were δ-selective opioid antagonists in vitro and bound selectively to δ receptors. The tetrahydroindole derivative 5, while δ-selective, was considerably less potent than its indole analogue 13. The data for 2-4 indicate that heterocycles other than pyrrole can serve as a spacer for the δ address moiety. Moreover, the lower δ antagonist potency of 5 illustrates the importance of the aromatic address component. Molecular dynamics simulations of enkephalin using a zipper binding model are consistent with a i address subsite that may accommodate the benzene moiety of NTI or the Phe4 phenyl group of leucine enkephalin. The considerably lower & opioid receptor antagonist potencies of the 6-aryl derivatives 6-8 are consistent with the conformational mobility of the aryl group and its location in the molecule.

Original languageEnglish (US)
Pages (from-to)1715-1720
Number of pages6
JournalJournal of medicinal chemistry
Volume34
Issue number5
DOIs
StatePublished - May 1 1991

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