ABSTRACT
The purpose of the present study was the synthesis and the biological screening of new analogues of N/OFQ(1-13)NH2, the minimal sequence maintaining the same activity as the natural peptide nociceptin. In order to investigate the role of Lys, we substituted Lys at positions 9 and/or 13 by Orn, Dab (diaminobutanoic acid) or Dap (diaminopropanoic acid). The new N/OFQ(1-13)NH2 analogues exerted strong and naloxone-resistant inhibition of electrically evoked contractions of rat vas deferens. Lys replacement with Orn maintained or even enhanced the inhibitory activity, while replacements with Dab and Dap decreased inhibitory activity.
Subject(s)
Opioid Peptides/chemical synthesis , Opioid Peptides/pharmacology , Peptide Fragments/chemical synthesis , Peptide Fragments/pharmacology , Opioid Peptides/chemistry , Peptide Fragments/chemistry , Receptors, Opioid/drug effectsABSTRACT
Previous studies have revealed that cannabinoid (CB)-receptor agonists inhibit gastric acid secretion stimulated by indirectly acting agents, but not by histamine. Aiming to investigate whether central or peripheral mechanisms are involved, the effects of the synthetic CB-receptor agonists WIN55,212-2 and HU-210, administered either intracerebroventricularly (i.c.v.) or intravenously (i.v.) to the anaesthetized rat with lumen-perfused stomach, against gastric acid secretion induced by pentagastrin were tested. Injected i.c.v., both WIN55,212-2 (50 and 100 microg/kg) and HU-210 (25, 50 and 100 microg/kg) were ineffective on either basal secretion or acid output induced by pentagastrin (7.7 microg/kg, i.v.). By contrast, i.v. injections of WIN55,212-2 (100 and 1000 microg/kg) or HU-210 (10-100 microg/kg) significantly inhibited pentagastrin-induced acid secretion, maximal reductions being 75.70 and 82.24% for WIN55,212-2 and HU-210, respectively. The gastric antisecretory effect of HU-210 was prevented by administration of the selective CB(1)-receptor antagonist SR141716A (1000 microg/kg, i.v.). These results show that CB(1)-receptors mediating inhibition of gastric acid secretion in the rat are mainly peripherally located.
