Synthesis, opioid receptor binding, and bioassay of naltrindole analogues substituted in the indolic benzene moiety

Subramaniam Ananthan, Cheryl A. Johnson, Ronald L. Carter, Sarah D. Clayton, Kenner C. Rice, Heng Xu, Peg Davis, Frank Porreca, Richard B. Rothman

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28 Scopus citations

Abstract

A series of analogues of the δ opioid receptor antagonist naltrindole (1) possessing a phenyl, phenoxy, or benzyloxy group at the 4'-, 5'-, 6'-, or - 7'-positions (4-15) and a 2-(2-pyridinyl)ethenyl group at the 5'-position (16) on the indolic benzene ring were synthesized through Fischer indolization of naltrexone. Compounds 4-16 were evaluated for their affinities in opioid receptor binding assays in rat or guinea pig brain membranes and for their opioid antagonist and agonist activities in vitro on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. All of the compounds displayed δ selectivity in binding to the δ, μ, and κ opioid receptors. The binding potencies of most of the compounds at the δ, μ, and κ sites, however, were lower than that of 1. Among positional isomers, the 7'-substituted compounds in general had higher affinities than 6'-, 5'-, or 4'-substituted analogues, indicating that bulky groups are tolerated better at the 7'-position than at other positions. The affinity of the compounds were also determined at putative subtypes of the δ and κ receptors: δ(cx-1) (μ-like), δ(cx-2) (δ-like), and the κ(2b) site in an attempt to identify subtype selective agents. Although none were identified, the data revealed a different rank-order of potency between μ vs δ(cx-1), δ(cx-2) vs δ, and the κ(2b) vs μ, δ, and κ1. The antagonist potencies of the compounds in the MVD were in agreement with their binding affinities at the δ site in rat brain membrane. The most potent member of the series, the 7'-phenoxy compound 14, binds to the δ site with a K(i) of 0.71 nM, shows > 40-fold δ over μ and δ over κ binding selectivity, and exhibits δ receptor antagonist potency in the MVD with a K(e) of 0.25 nM, properties which are comparable to the δ receptor affinity and antagonist potency of naltrindole (K(i) = 0.29 nM, K(e) = 0.49 nM). Interestingly, many members of the series were found to possess significant partial to full agonist activities in the MVD (6, 9, 10, 13, 16) or GPI (6, 11, 14, 15). Among the compounds studied, the highest agonist activity in the MVD was displayed by 16 (IC50 = 220 nM), and the highest agonist activity in the GPI was displayed by 14 (IC50 = 450 nM). The overall affinity and activity profile of compound 14 is, therefore, that of a nonpeptide ligand possessing mixed μ agonist/δ antagonist properties. Recently there has been considerable interest in such compounds possessing μ agonist/δ antagonist activities because of their potential therapeutic usefulness as analgesics with low propensity to produce tolerance and dependence side effects. The results of the present study suggest that morphinan derivatives related to 16 and 14 may provide useful leads for the development of potent nonpeptide ligands possessing δ agonist or mixed δ antagonist/μ agonist activities.

Original languageEnglish (US)
Pages (from-to)2872-2881
Number of pages10
JournalJournal of Medicinal Chemistry
Volume41
Issue number15
DOIs
StatePublished - Jul 16 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Ananthan, S., Johnson, C. A., Carter, R. L., Clayton, S. D., Rice, K. C., Xu, H., Davis, P., Porreca, F., & Rothman, R. B. (1998). Synthesis, opioid receptor binding, and bioassay of naltrindole analogues substituted in the indolic benzene moiety. Journal of Medicinal Chemistry, 41(15), 2872-2881. https://doi.org/10.1021/jm980083i