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 [Nphe(1)]-NC(1-13)-NH2 was prepared and tested for agonistic and antagonistic activities in the mo use vas deferens, a preparation that shows high sensitivity to nociceptin a nd related peptides. The purpose of this study was to determine the role of the aromatic residue at the N-terminal for antagonism and eventually ident ify compounds with improved potency. Results indicated that all 23 compound s are inactive as agonists, and the antagonistic potency of the initial tem plate [Nphe(1)]-NC(1-13)-NH2 is high (pK(B) 6.43) compared with those of al l other compounds except [(S)(beta Me)Nphe(1)]NC(1 -13)-NH2 (pK(B) 6.48). T he other 22 compounds can be divided into two groups: 10 show antagonistic potencies (pK(B)) 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 v ery critical for the interaction with the ORL1 receptor and can not be enla rged or sterically modified without significant loss of antagonistic potenc y.