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, Victor J Hruby, T. F. Burks

Research output: Contribution to journalArticle

59 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Vas Deferens
mu Opioid Receptor
Cytidine Triphosphate
Ileum
Guinea Pigs
D-Penicillamine (2,5)-Enkephalin
Somatostatin
Naloxone
phenylalanylleucine
Narcotic Antagonists
In Vitro Techniques
Biological Assay
Peptides

ASJC Scopus subject areas

  • Pharmacology

Cite this

Pharmacologic evaluation of a cyclic somatotatin analog with antagonist activity at Mu opioid receptors in vitro. / Shook, J. E.; Pelton, J. T.; Wire, W. S.; Hirning, L. D.; Hruby, Victor J; Burks, T. F.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 240, No. 3, 1987, p. 772-777.

Research output: Contribution to journalArticle

@article{6756a21b3e9f41328c385f2c3fb9f125,
title = "Pharmacologic evaluation of a cyclic somatotatin analog with antagonist activity at Mu opioid receptors in vitro",
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.",
author = "Shook, {J. E.} and Pelton, {J. T.} and Wire, {W. S.} and Hirning, {L. D.} and Hruby, {Victor J} and Burks, {T. F.}",
year = "1987",
language = "English (US)",
volume = "240",
pages = "772--777",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Pharmacologic evaluation of a cyclic somatotatin analog with antagonist activity at Mu opioid receptors in vitro

AU - Shook, J. E.

AU - Pelton, J. T.

AU - Wire, W. S.

AU - Hirning, L. D.

AU - Hruby, Victor J

AU - Burks, T. F.

PY - 1987

Y1 - 1987

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0023095079&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023095079&partnerID=8YFLogxK

M3 - Article

VL - 240

SP - 772

EP - 777

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -