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N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands.
J Med Chem 2005; 48(5):1421-7JM

Abstract

Previous structure-activity studies on nociceptin/orphanin FQ (N/OFQ) identified [Phe(1)Psi(CH(2)NH)Gly(2)]N/OFQ(1-13)-NH(2) and [Nphe(1)]N/OFQ(1-13)-NH(2) as a N/OFQ peptide receptor (NOP) partial agonist and pure antagonist, respectively. The addition of fluorine to the Phe(4) or the insertion of a further pair of basic amino acids Arg(14)-Lys(15) generate potent agonists. On the basis of these findings, we combined in the N/OFQ-NH(2) template the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) that increase the agonist potency with those conferring partial agonist (Phe(1)Psi(CH(2)NH)Gly(2)) or pure antagonist (Nphe(1)) properties. Twelve peptides were synthesized and pharmacologically evaluated in Chinese hamster ovary cells expressing the human recombinant NOP and in electrically stimulated mouse vas deferens and guinea pig ileum assays. All peptides behaved as NOP ligands; the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) increased ligand affinity/potency. Peptides with the normal Phe(1)-Gly(2) peptide bond behaved as full agonists, and those with the Phe(1)Psi(CH(2)NH)Gly(2) modification behaved as partial agonists, while those with the Nphe(1) modification behaved as partial agonists or pure antagonists depending on the presence or absence of the (pF)Phe(4) modification, respectively. The full agonist [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), the partial agonist [Phe(1)Psi(CH(2)NH)Gly(2),(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), and the pure antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) represent the most potent peptide ligands for NOP.

Authors+Show Affiliations

Department of Pharmaceutical Sciences and Biotechnology Center and Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Centre, University of Ferrara, 44100 Ferrara, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15743186

Citation

Guerrini, Remo, et al. "N- and C-terminal Modifications of Nociceptin/orphanin FQ Generate Highly Potent NOP Receptor Ligands." Journal of Medicinal Chemistry, vol. 48, no. 5, 2005, pp. 1421-7.
Guerrini R, Caló G, Lambert DG, et al. N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands. J Med Chem. 2005;48(5):1421-7.
Guerrini, R., Caló, G., Lambert, D. G., Carrá, G., Arduin, M., Barnes, T. A., ... Salvadori, S. (2005). N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands. Journal of Medicinal Chemistry, 48(5), pp. 1421-7.
Guerrini R, et al. N- and C-terminal Modifications of Nociceptin/orphanin FQ Generate Highly Potent NOP Receptor Ligands. J Med Chem. 2005 Mar 10;48(5):1421-7. PubMed PMID: 15743186.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands. AU - Guerrini,Remo, AU - Caló,Girolamo, AU - Lambert,David G, AU - Carrá,Giacomo, AU - Arduin,Marika, AU - Barnes,Tim A, AU - McDonald,John, AU - Rizzi,Daniela, AU - Trapella,Claudio, AU - Marzola,Erika, AU - Rowbotham,David J, AU - Regoli,Domenico, AU - Salvadori,Severo, PY - 2005/3/4/pubmed PY - 2005/4/12/medline PY - 2005/3/4/entrez SP - 1421 EP - 7 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 48 IS - 5 N2 - Previous structure-activity studies on nociceptin/orphanin FQ (N/OFQ) identified [Phe(1)Psi(CH(2)NH)Gly(2)]N/OFQ(1-13)-NH(2) and [Nphe(1)]N/OFQ(1-13)-NH(2) as a N/OFQ peptide receptor (NOP) partial agonist and pure antagonist, respectively. The addition of fluorine to the Phe(4) or the insertion of a further pair of basic amino acids Arg(14)-Lys(15) generate potent agonists. On the basis of these findings, we combined in the N/OFQ-NH(2) template the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) that increase the agonist potency with those conferring partial agonist (Phe(1)Psi(CH(2)NH)Gly(2)) or pure antagonist (Nphe(1)) properties. Twelve peptides were synthesized and pharmacologically evaluated in Chinese hamster ovary cells expressing the human recombinant NOP and in electrically stimulated mouse vas deferens and guinea pig ileum assays. All peptides behaved as NOP ligands; the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) increased ligand affinity/potency. Peptides with the normal Phe(1)-Gly(2) peptide bond behaved as full agonists, and those with the Phe(1)Psi(CH(2)NH)Gly(2) modification behaved as partial agonists, while those with the Nphe(1) modification behaved as partial agonists or pure antagonists depending on the presence or absence of the (pF)Phe(4) modification, respectively. The full agonist [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), the partial agonist [Phe(1)Psi(CH(2)NH)Gly(2),(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), and the pure antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) represent the most potent peptide ligands for NOP. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/15743186/N__and_C_terminal_modifications_of_nociceptin/orphanin_FQ_generate_highly_potent_NOP_receptor_ligands_ L2 - https://dx.doi.org/10.1021/jm040106v DB - PRIME DP - Unbound Medicine ER -