Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with Cα,α-dialkylated amino acids
Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with Cα,α-dialkylated amino acids
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DOI：
10.1016/j.bmc.2007.04.026
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发表时间：
2007-07-01
影响因子：
3.5
通讯作者：
Salvadori, Severo
中科院分区：
文献类型：
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作者：
Arduin, Marika;Spagnolo, Barbara;Salvadori, Severo
以往对伤害素/孤啡肽FQ(N/OFQ)的构效关系和核磁共振研究表明，Ala(7)和/或Ala(11)的AIB取代通过α螺旋结构诱导机制增加了多肽的效力。在此基础上，我们合成了一系列N/OFQ-NH2类似物，并在小鼠输精管实验中进行了药理评价。在20个新的N/OFQ类似物中，没有一个比[AIB(7)]N/OFQ-NH2产生更好的结果。因此，该取代与已知的调节多肽效力和/或功效产生化合物21[Nphe(1)AIB(7)Arg(14)Lys(15)]N/OFQ-NH2(编码为UFP-111)的化学修饰相结合，化合物22[(PF)Phe(4)AIB(7)Arg(14)Lys(15)]N/OFQ-NH2(UFP-112)和化合物23[Phe psi(CH2-NH)Gly(2)(PF)Phe(4)AIB(7)Arg(14)Lys(15)]N/OFQ-NH2(UFP-113)。在表达天然和重组NOP受体的药理制剂上进行的一系列体外功能测试中，这些新的多肽作为高效的NOP受体配体，显示出全部(UFP-112)和部分(UFP-113)激动剂和纯拮抗剂(UFP-111)的活性。(C)2007爱思唯尔有限公司。保留所有权利。
Previous structure-activity and NMR studies on nociceptin/orphanin FQ (N/OFQ) demonstrated that Aib substitution of Ala(7) and/or Ala(11) increases the peptide potency through an alpha helix structure induction mechanism. On these bases we synthesised and evaluated pharmacologically in the mouse vas deferens assay a series of N/OFQ-NH2 analogues substituted in position 7 and 11 with C alpha,alpha-disubstituted cyclic, linear and branched amino acids. None of the 20 novel N/OFQ analogues produced better results than [Aib(7)]N/OFQ-NH2. Thus, this substitution was combined with other chemical modifications known to modulate peptide potency and/or efficacy generating compound 21 [Nphe(1)Aib(7) Arg(14) Lys(15)] N/OFQ-NH2 (coded as UFP- 111), compound 22 [(pF)Phe(4) Aib(7) Arg(14) Lys(15)] N/OFQ-NH2 (UFP-112) and compound 23 [Phe psi(CH2-NH)Gly(2) (pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH2 (UFP- 113). These novel peptides behaved as highly potent NOP receptor ligands showing full (UFP- 112) and partial (UFP- 113) agonist and pure antagonist (UFP- 111) activities in a series of in vitro functional assays performed on pharmacological preparations expressing native as well as recombinant NOP receptors. (c) 2007 Elsevier Ltd. All rights reserved.