Species differences in the efficacy of compounds at the nociceptin receptor (ORL1)

Recent studies have identified compounds with reduced efficacy relative to nociceptin/orphanin FQ at the opioid-like receptor ORL1. Utilizing stimulation of [(35)S]GTPgammaS binding as in vitro assays, it was determined that both [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2) and the hexapeptide Ac-RYYRIK-NH(2) act as partial agonists in CHO cells transfected with either human or mouse ORL1. Maximal activity for both [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2) and Ac-RYYRIK-NH(2) was significantly greater in cells transfected with the human receptor (90% and 73% in a high expressing clone, 76% and 68% in low expressing clone) rather than the mouse receptor (37.5 and 33%), regardless of receptor number in individual clones. In vitro studies in cells transfected with exaggerated receptor numbers can lead to unreliable estimates of agonist and antagonist activity, however, these studies suggest that animal experiments on the activity of novel compounds may not always be better predictors of the ultimate activity in humans.