Pharmacologic evaluation of a cyclic somatotatin analog with antagonist activity at Mu opioid receptors in vitro

J. E. Shook, J. T. Pelton, W. S. Wire, L. D. Hirning, V. J. Hruby, T. F. Burks

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

The cyclic somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) was evaluated for agonist and opioid antagonist actions and receptor selectivity in two bioassays: electrically stimulated guinea pig isolated ileum (GPI) and mouse isolated vas deferens (MVD). CTP (100, 300, 1000 nM) produced concentration-dependent antagonism of the mu agonist [Me-PHe3,D-Pro4]morphiceptin (PL017) in both the GPI and MVD. Schild analysis of the interactions between CTP and PL017 indicated competitive antagonism between these peptides (Schild slope GPI -0.97 ± 0.16, Schild slope MVD -1.4 ± 0.4), and also suggested that the mu receptors in the two tissues are not different (pA2 GPI 7.1 ± 0.17, pA2 MVD 6.9 ± 0.16). The effects of the delta selective agonist [D-Pen2,D-Pen5]enkephalin in the MVD were not antagonized by CTP. Likewise, in the GPI, CTP did not antagonize the kappa agonist (trans-3-4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamine (U50,488H). In comparison, naloxone antagonized both PL017 and U50,488H in the GPI, as well as [D-Pen2,D-Pen5]enkephalin and PL017 in the MVD. In the MVD, CTP also exerted weak somatostatin-like actions (35% maximal inhibition) that could not be demonstrated in somatostatin-tolerant tissues. It also showed inhibitory actions at very high concentrations (3000 and 10,000 nM) that were blocked by both naloxone and the delta antagonist N,N-diallyl-Tyr-AIB-AIB-Phe-Leu-OH (ICI 174,864). ICI 174,864 antagonized [D-Pen2,D-Pen5]enkephalin in the MVD, but did not affect PL017. These results indicate that CTP is a selective mu receptor antagonist in vitro. These findings also emphasize the importance of receptor-selective antagonists such as CTP in characterizing the receptor populations in a tissue and provide an additional approach for evaluating the receptor selectivity of putative receptor-selective agonists.

Original languageEnglish (US)
Pages (from-to)772-777
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume240
Issue number3
StatePublished - 1987

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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