Comparison of the structure-activity relationships of nociceptin and dynorphin A using chimeric peptides

• Published in: FEBS letters Vol. 417; no. 3; pp. 333 - 336
• Main Authors: Lapalu, Sophie, Moisand, Christiane, Mazarguil, Honoré, Cambois, Gilles, Mollereau, Catherine, Meunier, Jean-Claude
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 17.11.1997
• Subjects: Amino Acid Sequence; Animals; Binding, Competitive; Cell Membrane - metabolism; Chimeric neuropeptide; CHO Cells; Cricetinae; Diprenorphine - metabolism; dyn; Dynorphin A; dynorphin A/nociceptin hybrid peptide; Dynorphins - chemistry; Dynorphins - pharmacology; Humans; Kinetics; Molecular Sequence Data; noc; Nociceptin; Nociceptin Receptor; nociceptin/dynorphin A hybrid peptide; Nociceptin/orphanin FQ; Opioid and opioid receptor-like receptor; Opioid Peptides - chemistry; Opioid Peptides - pharmacology; opioid receptor-like 1; ORL1; Peptides - pharmacology; Receptors, Opioid - biosynthesis; Receptors, Opioid - physiology; Receptors, Opioid, kappa - biosynthesis; Receptors, Opioid, kappa - physiology; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - pharmacology; Recombinant Proteins - biosynthesis; Sequence Alignment; Structure-Activity Relationship; Chimeric neuropeptide; noc; Structure-activity relationship; nd; dyn; Dynorphin A; Nociceptin/orphanin FQ; Opioid and opioid receptor-like receptor; dn; ORL1
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(97)01318-5

The aim of the present study was to delineate the functional domains of nociceptin (noc), a neuropeptide which is structurally related to dynorphin A (dyn). The binding and biological potencies towards the nociceptin (ORL1) and dynorphin A ( κ-opioid) receptors of twenty dyn/noc and noc/dyn hybrid peptides were compared with those of the parent heptadecapeptides. Replacement of as many as eleven residues in the C-terminus of dynorphin by the corresponding nociceptin sequence has no significant effect on binding and biological activity towards the κ-opioid receptor. In marked contrast, replacement of as few as six residues (RKLANQ) in the C-terminus of nociceptin by the corresponding dynorphin sequence (LKWDNQ) dramatically impairs both affinity and activity towards the ORL1 receptor. This clearly indicates that the two neuropeptides have different functional architectures, despite the dual structural homology of both ligands and receptors. Moreover, the recombinant peptide approach led us to identify hybrids whose sequences differ only at positions 5 and 6 and displaying opposite or no receptor selectivity. One contains the dynorphin Leu 5-Arg 6 sequence and prefers the κ-opioid receptor, whereas the other comprises the nociceptin Thr 5-Gly 6 sequence and prefers the ORL1 receptor. A third, containing the mixed dynorphin/nociceptin Leu 5-Gly 6 sequence, does not discriminate between the two types of receptor.