Structure–activity studies on different modifications of nociceptin/orphanin FQ: Identification of highly potent agonists and antagonists of its receptor

• Published in: Regulatory peptides Vol. 130; no. 3; pp. 116 - 122
• Main Authors: Chang, Min, Peng, Ya-li, Dong, Shou-liang, Han, Ren-wen, Li, Wei, Yang, Ding-jian, Chen, Qiang, Wang, Rui
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 15.09.2005; Amsterdam Elsevier
• Subjects: Analogues; Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Cell Membrane - metabolism; Electric Stimulation; Excitatory Amino Acids - agonists; Fundamental and applied biological sciences. Psychology; Ligands; Male; Mice; Mouse vas deferens; Nociceptin; Nociceptin Receptor; Nociceptin/orphanin FQ (N/OFQ); Nociceptin/orphanin FQ receptor (NOP); Opioid Peptides - metabolism; Peptide Fragments - metabolism; Rat brain membranes; Rats; Rats, Wistar; Receptors, Opioid - agonists; Receptors, Opioid - chemistry; Structure-Activity Relationship; Vas Deferens - physiology; Vasodilator Agents - metabolism; Vertebrates: endocrinology; Nociceptin/orphanin FQ receptor (NOP); Mouse vas deferens; Analogues; Nociceptin/orphanin FQ (N/OFQ); Rat brain membranes; Semen pathway; Agonist; Rat; Rodentia; Central nervous system; Male genital duct; Male genital system; Vas deferens; Encephalon; Nociceptin; Vertebrata; Mammalia; Mouse; N/OFQ receptor; Animal; Antagonist; Biological receptor
• ISSN: 0167-0115; 1873-1686
• DOI: 10.1016/j.regpep.2005.04.005

Nociceptin/orphanin FQ (N/OFQ) and its receptor system modulate a variety of biological functions and further understandings of physiological and pathological roles of this system require new potent agonists and antagonists of its receptor. Two series of N/OFQ related analogues were synthesized to investigate the relationship of different modifications. We combined modifications including: (a) Phe 4→(pF)Phe 4; (b) Ala 7, Ala 11→Aib 7, Aib 11; (c) Leu 14, Ala 15→Arg 14, Lys 15. Compared with the first series, N-terminus of the second series was changed from Phe 1 to Nphe 1. All the analogues were amidated at C-terminus. These compounds were tested in binding studies on rat brain membranes and mouse vas deferens assay. Results indicated that the compounds of the first series showed higher affinity and potency than N/OFQ (p K i = 9.33; pEC 50 = 7.50). In particular, [(pF)Phe 4, Aib 7, Aib 11, Arg 14, Lys 15] N/OFQ-NH 2 was found to be a highly potent agonist with p K i = 10.78 in binding studies and pEC 50 = 9.37 in mouse vas deferens assay. The second series all competitively antagonized the effects of N/OFQ in mouse vas deferens assay. [Nphe 1, (pF)Phe 4, Aib 7, Aib 11, Arg 14, Lys 15] N/OFQ-NH 2 was the best antagonist with p A 2 = 8.39 and showed high binding affinity with p K i = 9.99. Thus modifications which increase the potency of agonist have synergistic effect on biological activity and a replacement of N-terminus leads to shift of analogues from agonist to antagonist.