کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1362833 | 981497 | 2007 | 10 صفحه PDF | دانلود رایگان |
Previous structure–activity and NMR studies on nociceptin/orphanin FQ (N/OFQ) demonstrated that Aib substitution of Ala7 and/or Ala11 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 Cα,α-disubstituted cyclic, linear and branched amino acids. None of the 20 novel N/OFQ analogues produced better results than [Aib7]N/OFQ-NH2. Thus, this substitution was combined with other chemical modifications known to modulate peptide potency and/or efficacy generating compound 21 [Nphe1Aib7Arg14Lys15]N/OFQ-NH2 (coded as UFP-111), compound 22 [(pF)Phe4Aib7Arg14Lys15]N/OFQ-NH2 (UFP-112) and compound 23 [Phe1Ψ(CH2–NH)Gly2(pF)Phe4Aib7Arg14Lys15]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.
Two series of compounds substituted in position 7 or 11 with Cα,α-disubstituted amino acids were synthesised and pharmacologically evaluated; new potent NOP receptor agonists were identified.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 13, 1 July 2007, Pages 4434–4443