Arduin Marika, Spagnolo Barbara, Calò Girolamo, Guerrini Remo, Carrà Giacomo, Fischetti Carmela, Trapella Claudio, Marzola Erika, McDonald John, Lambert David G, Regoli Domenico, Salvadori Severo
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy.
Bioorg Med Chem. 2007 Jul 1;15(13):4434-43. doi: 10.1016/j.bmc.2007.04.026. Epub 2007 Apr 24.
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-NH(2) analogues substituted in position 7 and 11 with Calpha,alpha-disubstituted cyclic, linear and branched amino acids. None of the 20 novel N/OFQ analogues produced better results than [Aib(7)]N/OFQ-NH(2). 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-NH(2) (coded as UFP-111), compound 22 [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112) and compound 23 [Phe(1)Psi(CH(2)-NH)Gly(2)(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (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.
先前对孤啡肽/孤啡肽FQ（N/OFQ）的构效关系及核磁共振研究表明，用Aib取代Ala(7)和/或Ala(11)可通过诱导α螺旋结构的机制提高肽的效力。基于这些研究结果，我们合成了一系列在第7位和第11位被α,α-二取代的环状、线性和支链氨基酸取代的N/OFQ-NH(2)类似物，并在小鼠输精管试验中对其进行了药理学评估。这20种新型N/OFQ类似物中，没有一种比[Aib(7)]N/OFQ-NH(2)产生更好的结果。因此，将这种取代与其他已知可调节肽效力和/或功效的化学修饰相结合，得到了化合物21 [Nphe(1)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2)（编码为UFP-111）、化合物22 [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2)（UFP-112）和化合物23 [Phe(1)Psi(CH(2)-NH)Gly(2)(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2)（UFP-113）。在对表达天然及重组NOP受体的药理制剂进行的一系列体外功能试验中，这些新型肽表现为高效的NOP受体配体，具有完全（UFP-112）和部分（UFP-113）激动剂以及纯拮抗剂（UFP-111）活性。
