Structure-activity relationship of [Nphe(1)]-NC-(1-13)-NH2, a pure and selective nociceptin/orphanin FQ receptor antagonist

A series of analogs of the ORL1 receptor antagonist [Nphe1]-NC(1-13)-NH2 was prepared and tested for agonistic and antagonistic activities in the mouse vas deferens, a preparation that shows high sensitivity to nociceptin and related peptides. The purpose of this study was to determine the role of the aromatic residue at the N-terminal for antagonism and eventually identify compounds with improved potency. Results indicated that all 23 compounds are inactive as agonists, and the antagonistic potency of the initial template [Nphe1]- NC(1-13)-NH2 is high (pKB 6.43) compared with those of all other compounds except [(S)(bMe)Nphe1]NC(1-13)-NH2 (pKB 6.48). The other 22 compounds can be divided into two groups: 10 show antagonistic potencies (pKB) ranging from 5.30 to 5.86, whereas the other 12 compounds are inactive. This study clearly shows that the aromatic ring of Nphe is very critical for the interaction with the ORL1 receptor and can not be enlarged or sterically modi®ed without signi®cant loss of antagonistic potency.