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

被引:48
作者
Berger, H
Albrecht, E
Wallukat, G
Bienert, M
机构
[1] Res Inst Mol Pharmacol, D-10315 Berlin, Germany
[2] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany
关键词
nociceptin; orphanin FQ; S-35]-GTP gamma S; rat brain membranes; rat cardiomyocytes; acetyl-RYYRIK-NH2; antagonism;
D O I
10.1038/sj.bjp.0702353
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 [S-35]-GTP gamma S 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 mu-, delta-, and kappa-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.
引用
收藏
页码:555 / 558
页数:4
相关论文
共 12 条
[1]  
Albrecht E, 1998, J PHARMACOL EXP THER, V286, P896
[2]   Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more [J].
Darland, T ;
Heinricher, MM ;
Grandy, DK .
TRENDS IN NEUROSCIENCES, 1998, 21 (05) :215-221
[3]  
Dooley CT, 1997, J PHARMACOL EXP THER, V283, P735
[4]   A new selective antagonist of the nociceptin receptor [J].
Guerrini, R ;
Calo, G ;
Rizzi, A ;
Bigoni, R ;
Bianchi, C ;
Salvadori, S ;
Regoli, D .
BRITISH JOURNAL OF PHARMACOLOGY, 1998, 123 (02) :163-165
[5]   ISOLATION AND STRUCTURE OF THE ENDOGENOUS AGONIST OF OPIOID RECEPTOR-LIKE ORL(1) RECEPTOR [J].
MEUNIER, JC ;
MOLLEREAU, C ;
TOLL, L ;
SUAUDEAU, C ;
MOISAND, C ;
ALVINERIE, P ;
BUTOUR, JL ;
GUILLEMOT, JC ;
FERRARA, P ;
MONSARRAT, B ;
MAZARGUIL, H ;
VASSART, G ;
PARMENTIER, M ;
COSTENTIN, J .
NATURE, 1995, 377 (6549) :532-535
[6]   Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor [J].
Meunier, JC .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1997, 340 (01) :1-15
[7]   ORPHANIN-FQ - A NEUROPEPTIDE THAT ACTIVATES AN OPIOID-LIKE G-PROTEIN-COUPLED RECEPTOR [J].
REINSCHEID, RK ;
NOTHACKER, HP ;
BOURSON, A ;
ARDATI, A ;
HENNINGSEN, RA ;
BUNZOW, JR ;
GRANDY, DK ;
LANGEN, H ;
MONSMA, FJ ;
CIVELLI, O .
SCIENCE, 1995, 270 (5237) :792-794
[8]   Excitement over orphanin FQ/nociceptin [J].
Rowe, PM .
LANCET, 1996, 347 (9001) :606-606
[9]   IN-VITRO AUTORADIOGRAPHY OF RECEPTOR-ACTIVATED G-PROTEINS IN RAT-BRAIN BY AGONIST-STIMULATED GUANYLYL 5'-[GAMMA-[S-35]THIO]TRIPHOSPHATE BINDING [J].
SIM, LJ ;
SELLEY, DE ;
CHILDERS, SR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (16) :7242-7246
[10]  
Taylor F, 1998, NEUROREPORT, V9, pR65