Structure-activity relationships of nociceptin and related peptides: comparison with dynorphin A

Nociceptin and its receptor (OP4) share sequence homologies with the opioid peptide ligand dynorphin A and its receptor OP2. Cationic residues in the C-terminal sequence of both peptides seem to be required for selective receptor occupation, but the number and the distribution of these basic residues are different and quite critical. Both receptors are presumably activated by the peptides N-terminal sequence (Xaa-Gly Gly-Phe, where Xaa 5 Phe or Tyr); however, although OP4 requires Phe4 as a determinant pharmacophore, OP2 requires Tyr1 as do the other opioid receptors. An extensive structure-activity analysis of the N-terminal tetrapeptide has led to conclude that the presence of aromatic residues in position one and four, preferably Phe, as well as the distance between Phe1 and Phe4 are extremely critical for occupation and activation of OP4 in contrast with other opioid receptors (e.g. OP1, OP3, OP2). Modification of distance between the side chains of Phe1 and Phe4 (as obtained with Nphe1 substitution in both NC and NC(1–13)-NH2) and/or conformational orientation of Phe1 (as in Phe1c(CH2-NH)-Gly2) has brought to discovery of pure antagonist ([Nphe1]-NC(1–13)-NH2) and a partial agonist ([Phe1 c(CH2- NH)-Gly2]-NC(1–13)-NH2), which have allowed us to characterize and classify the OP4 receptor in several species. Thus, although antagonist activities at the OP4 receptor are obtained by chemical modification of Phe1-Gly2 peptide bond or by a shift of Phe1 side chain of NC peptides, antagonism at the OP2 receptor requires the diallylation of the N-terminal amino function, for instance, of dynorphin A. These considerations support the interpretation that the two systems nociceptin/OP4 and dynorphin A/OP2 are distinct pharmacological entities that differs in both their active sites (Tyr1 for Dyn A and Phe4 for NC) and the number and position of cationic residues in the C-terminal portions of the molecules. The chemical features of novel OP4 receptor ligands either pseudopeptides obtained by combinatorial library screening or molecules of nonpeptide structure are reported and discussed in comparison with NC and NC related peptides.