Synthesis of Highly μ and δ Opioid Receptor Selective Peptides Containing a Photoaffinity Group

Geoffrey Landis, George Lui, Jennifer E. Shook, Henry I. Yamamura, Thomas F. Burks, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

A series of cyclic, conformationally constrained photolabile peptides related to the enkephalins and to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the δ and μ opioid receptors. The following new peptides were prepared and tested for their δ opioid receptor potency and selectivity in the guinea pig ileum assay, the mouse vas deferens assay, and the rat brain binding assay: H-Tyr-D-Pen-Gly-p-NH2Phe-D-Pen-OH (1, [p-NH2Phe4]DPDPE) and H-Tyr-D-Pen-Gly-p-N3Phe-D-Pen-OH (2, [p-N3Phe4]-DPDPE). The following new peptides were prepared and tested for their μ opioid receptor potency and selectivity in the same assays: H-D-Phe-Cys-p-NH2Phe-D-Trp-Lys-Thr-Pen-Thr-NH2(3, [p-NH2Phe3]CTP) and D-Phe-Cys-p-N3Phe-D-Trp-Lys-Thr-Pen-Thr-NH2(4, [p-N3Phe3]CTP). The δ selective photoaffinity peptide 2 displayed both high affinity (IC50= 9.5 nM) and good selectivity (IC50μ/IC50δ= 1053) as an agonist at δ opioid receptors in bioassays, and 2 also displayed moderate affinity (33 nM) and excellent selectivity (IC50μ/IC50δ = 110) for rat brain δ opioid receptors. The μ selective photoaffinity peptide 4 displayed very weak affinity (8% contraction at 300 nM) at μopioid receptors in bioassays, but good affinity (IC50= 48.6 nM) and excellent selectivity (IC50δ/IC50μ, = 412) for the rat brain μ opioid receptors. These conformationally constrained cyclic photoaffinity peptides may be useful tools to investigate the pharmacology of δ and μ opioid receptors.

Original languageEnglish (US)
Pages (from-to)638-643
Number of pages6
JournalJournal of Medicinal Chemistry
Volume32
Issue number3
DOIs
StatePublished - Mar 1 1989

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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