Structure-activity studies on different modifications of nociceptin/orphanin FQ: identification of highly potent agonists and antagonists of its receptor.

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 (pK(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 pK(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 pA(2)=8.39 and showed high binding affinity with pK(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.