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 speci®c antagonists will be most helpful. In this study it was found that the hexapeptide acetyl-RYYRIK-NH 2 (Ac-RYYRIK-NH 2 ), described in literature as partial agonist on ORL1 transfected in CHO cells, antagonizes the stimulation of [ 35 S]-GTPgS binding to G proteins by noc/OFQ in membranes and sections of rat brain. The antagonism of the peptide was competitive, of high a nity (Schild constant 6.58 nM), and speci®c for noc/OFQ in that the stimulation of GTP binding by agonists for the m-, d-, and k-opioid receptor was not inhibited. The hexapeptide also fully inhibited the chronotropic e ect of noc/OFQ on neonatal rat cardiomyocytes. It is suggested that Ac-RYYRIK-NH 2 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 speci®c antagonists.
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