Antagonism by acetyl‐RYYRIK‐NH2 of G protein activation in rat brain preparations and of chronotropic effect on rat cardiomyocytes evoked by nociceptin/orphanin FQ

• Published in: British journal of pharmacology Vol. 126; no. 3; pp. 555 - 558
• Main Authors: Berger, H, Albrecht, E, Wallukat, G, Bienert, M
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-1999; Nature Publishing
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer - pharmacology; [35S]‐GTPγS; acetyl‐RYYRIK‐NH2; Analgesics - pharmacology; Animals; antagonism; Binding, Competitive - drug effects; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cardiovascular Agents - pharmacology; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Dose-Response Relationship, Drug; Enkephalin, Ala-MePhe-Gly; Enkephalin, D-Penicillamine (2,5); Enkephalins - pharmacology; Fundamental and applied biological sciences. Psychology; GTP-Binding Proteins - drug effects; GTP-Binding Proteins - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Male; Membranes - drug effects; Membranes - metabolism; Middle Aged; Myocardium - cytology; Myocardium - metabolism; Nociceptin; Oligopeptides - pharmacology; Opioid Peptides - pharmacology; orphanin FQ; rat brain membranes; rat cardiomyocytes; Rats; Rats, Wistar; Receptors, Opioid - agonists; Receptors, Opioid, delta - agonists; Receptors, Opioid, kappa - agonists; Receptors, Opioid, mu - agonists; Special Reports; Sulfur Radioisotopes; Vertebrates: nervous system and sense organs; Heart; Peptides; Rat; Opioid receptor; Rodentia; Central nervous system; In vitro; Myocyte; Heart rate; Binding protein; Vertebrata; Mammalia; Animal; Frequency; Circulatory system; Brain (vertebrata); G protein
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0702353

For the further elucidation of the central functions of nociceptin/orphanin FQ (noc/OFQ), the endogenous ligand of the G protein‐coupled opioid receptor‐like receptor ORL1, centrally acting specific antagonists will be most helpful. In this study it was found that the hexapeptide acetyl‐RYYRIK‐NH2 (Ac‐RYYRIK‐NH2), described in literature as partial agonist on ORL1 transfected in CHO cells, antagonizes the stimulation of [35S]‐GTPγS binding to G proteins by noc/OFQ in membranes and sections of rat brain. The antagonism of the peptide was competitive, of high affinity (Schild constant 6.58 nM), and specific for noc/OFQ in that the stimulation of GTP binding by agonists for the μ‐, δ‐, and κ‐opioid receptor was not inhibited. The hexapeptide also fully inhibited the chronotropic effect of noc/OFQ on neonatal rat cardiomyocytes. It is suggested that Ac‐RYYRIK‐NH2 may provide a promising starting point for in vivo tests for antagonism of the action of noc/OFQ and for the further development of highly active and specific antagonists.
British Journal of Pharmacology (1999) 126, 555–558; doi:10.1038/sj.bjp.0702353