Structure-activity studies on nociceptin analogues: ORL1 receptor binding and biological activity of cyclic disulfide-containing analogues of nociceptin peptides.

Nociceptin/Orphanin FQ is an endogenous peptide ligand for the opioid receptor-like 1 (ORL1) receptor. To investigate the structural and conformational requirements of the nociceptin (NC)−receptor interaction, six cyclic analogues containing Cys disulfide linkages were designed and synthesized. Analogues cyclized at the N-terminal part, cyclo[Cys0, Cys7]NC(1−13)-NH2 (2) and cyclo[Cys0, Cys11]NC(1−13)-NH2 (4), and their corresponding linear peptides had very low activities in both the receptor binding and the GTPγS functional assays using human ORL1 transfected cell membranes. On the contrary, analogues cyclized at the C-terminal parts by the disulfide linkages at positions 6−10, 7−11, 7−14, and 10−14 sustained relatively high potencies in both assays. Notably, cyclo[Cys10, Cys14]NC(1−14)-NH2 (12) was found to be a potent NC agonist nearly as active as the parent peptide or NC. The maximum efficacy (Emax) of the C-terminally cyclized analogues and their linear counterparts in the GTPγS functional assay sho...