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

Citation
R. Guerrini et al., Structure-activity relationships of nociceptin and related peptides: comparison with dynorphin A, PEPTIDES, 21(7), 2000, pp. 923-933
Citations number
72
Categorie Soggetti
Biochemistry & Biophysics
Journal title
PEPTIDES
ISSN journal
01969781 → ACNP
Volume
21
Issue
7
Year of publication
2000
Pages
923 - 933
Database
ISI
SICI code
0196-9781(200007)21:7<923:SRONAR>2.0.ZU;2-Z
Abstract
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 rece ptor occupation, but the number and the distribution of these basic residue s are different and quite critical. Both receptors are presumably activated by the peptides N-terminal sequence (Xaa-Gly Gly-Phe, where Xaa = Phr or T yr); however, although OP4 requires Phe(4) as a determinant pharmacophore, OP2 requires Tyr(1) as do the other opioid receptors. An extensive structur e-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 Phe(1) and Phe(4) are extremely critical for occupation and activation of OP4 in contrast with other opioid receptor s (e.g. OP1, OP3, OP2). Modification of distance between the side chains of Phe(1) and Phe(4) (as obtained with Nphe(1) substitution in both NC and NC (1-13)-NH2) and/or conformational orientation of Phe(1) (as in Phr(1)psi(CH 2-NH)-Gly(2)) has brought to discovery of pure antagonist ([Nphe(1)]-NC(1-1 3)-NH2) and a partial agonist ([Phe(1) psi(CH2-NH)-Gly(2)]-NC(1-13)-NH2), w hich have allowed us to characterize and classify the OP4 receptor in sever al species. Thus, although antagonist activities at the OF, receptor are ob tained by chemical modification of Phe(1)-Gly(2) peptide bond or by a shift of Phe(1) side chain of NC peptides, antagonism at the OP2 receptor requir es the diallylation of the N-terminal amino function, for instance, of dyno rphin A. These considerations support the interpretation that the two syste ms nociceptin/OP4 and dynorphin A/OP2 are distinct pharmacological entities that differs in both their active sites (Tyr(1) for Dyn A and Phe(4) for N C) and the number and position of cationic residues in the C-terminal porti ons of the molecules. The chemical features of novel OP4 receptor ligands e ither pseudopeptides obtained by combinatorial library screening or molecul es of nonpeptide structure are reported and discussed in comparison with NC and NC related peptides. (C) 2000 Elsevier Science Inc. All rights reserve d.