title: Pharmacologic evaluation of a cyclic somatostatin 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)benzenea cetamine (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.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000294:innervation / Q000502:physiology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D013004:Somatostatin; C051868:phenylalanyl-cyclo(cysteinyl-tyrosyltryptophyl-lysyl-threonyl-penicillamine)threoninamide