Synthesis and structure-activity relationship of [Nle10] neurokinin A (4-10) analogs with constraint in the backbone and at position six

Ferenc Ötvös, Dmitry S. Gembitsky, Richard F. Murphy, Sándor Lovas

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Steric requirements of binding [Nle10]NKA(4-10) to NK-2 receptor were studied by introducing conformationally constrained amino acid analogs into its sequence. Two series of [Nle10]NKA(4-10) analogs were synthesized to investigate (i) the significance of a putative β-turn in the receptor-ligand interaction by insertion of either (S)- or (R)-Gly 8{ANC-2}Leu9 γ-lactams to mimic a β-turn constraint, and (ii) the effect of hindered rotation in the Φ, χ1 and χ2 dihedral angle space of the crucially important Phe6 which was replaced systematically with d-Phe, d- and l-Tyr, as well as with their conformationally constrained analogs, Tic, HOTic and β-MePhe. Competition binding experiments with [3H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. The analog possessing only an (R)-Gly8{ANC-2}Leu9 constraint, had the same binding affinity as that of the parent peptide. The rank order of potency of the other analogs showed a cumulative effect of different structural modifications in decreasing the binding affinity, i.e., when changing the configuration of the lactam ring to S, replacing Phe6 with constrained analogs, Tic or β-MePhe, changing the configuration of the amino acid at position six to d, and introducing a hydroxyl group on the aromatic ring.

Original languageEnglish (US)
Pages (from-to)329-336
Number of pages8
JournalInternational Journal of Peptide Research and Therapeutics
Issue number1-2
StatePublished - Jun 1 2007


All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Bioengineering
  • Biochemistry
  • Molecular Medicine
  • Drug Discovery

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