Incorporation of vinylogous scaffolds in the C-terminal tripeptide of substance P

  1. S. Claudel,
  2. O. Tasseau,
  3. S. Sagan,
  4. C. Grison†,
  5. P. Coutrot,
  6. S. Lavielle

Article first published online: 15 OCT 2004

DOI: 10.1111/j.1399-3011.2004.00180.x

Issue

The Journal of Peptide Research

The Journal of Peptide Research

Volume 64, Issue 5, pages 186–193, November 2004

Additional Information

How to Cite

Claudel, S., Tasseau, O., Sagan, S., Grison, C., Coutrot, P. and Lavielle, S. (2004), Incorporation of vinylogous scaffolds in the C-terminal tripeptide of substance P. The Journal of Peptide Research, 64: 186–193. doi: 10.1111/j.1399-3011.2004.00180.x

Author Information

  1. S. Claudel, C. Grison and P. Coutrot, Laboratoire de Chimie Organique Biomoléculaire, Institut Nancéien de Chimie Moléculaire, Université H. Poincaré, Vandoeuvre-les-Nancy Cedex, France O. Tasseau, S. Sagan and S. Lavielle, UMR 7613 CNRS-Université Paris VI, Structure et Fonction de Molécules Bioactives, Université Paris VI, Paris Cedex, France

  1. †

    Present address: Ecole Nationale Supérieure de Chimie de Montpellier, UMR 5032-ERT5, Laboratoire de Chimie Biomoléculaire, 8, rue de l'Ecole Normale, 34296 Montpellier, France

*S. Lavielle UMR 7613 CNRS/Paris VI, Case 182 Université P. et M. Curie 4, Place Jussieu 75005 Paris France Tel.: 33 1 44 27 55 35 Fax: 33 1 44 27 71 50 E-mail: lavielle@ccr.jussieu.fr

  • †

    Present address: Ecole Nationale Supérieure de Chimie de Montpellier, UMR 5032-ERT5, Laboratoire de Chimie Biomoléculaire, 8, rue de l'Ecole Normale, 34296 Montpellier, France

Publication History

  1. Issue published online: 5 DEC 2008
  2. Article first published online: 15 OCT 2004
  3. Dates: Received 2 April 2004 Revised 2 June 2004 Accepted 27 June 2004

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Keywords:

  • bioactive conformation;
  • NK-1 receptor;
  • substance P;
  • vinylogous scaffold

Abstract:  Glycine-9 and leucine-10 of substance P (SP) are critical for (NK)-1 receptor recognition and agonist activity. Proψ(Z)-CH=CH(CH3)-CONH)Leu (or Met) and Proψ((E)-CH=CH(CH3)-CONH)Leu (or Met) have been introduced in the sequence of SP, in order to restrict the conformational flexibility of the C-terminal tripeptide, Gly-Leu-Met-NH2, of SP. Proψ((Z)-CH=C(CH2CH(CH3)2)-CONH)Met-NH2, with an isobutyl substituent to mimic the Leu side-chain, was also incorporated in place of the C-terminal tripeptide. The substituted-SP analogs were tested for their affinity to human NK-1 receptor specific binding sites (NK-1M and NK-1m) and their potency to stimulate adenylate cyclase and phospholipase C in Chinese Hamster ovary (CHO) cells transfected with the human NK-1 receptor. The most potent SP analogs [Pro9ψ((Z)CH=C(CH3)CONH)Leu10]SP and [Pro9ψ ((E)CH=C(CH3)CONH)Leu10]SP, are about 100-fold less potent than SP on both binding sites and second messenger pathways. These vinylogous (Z)- or (E)-CH=C(CH3)- or (Z)-CH=C(CH2CH(CH3)2) moieties hamper the correct positioning of the C-terminal tripeptide of SP within both the NK-1M- and NK-1m-specific binding sites. The origin of these lower potencies is related either to an incorrect peptidic backbone conformation and/or an unfavorable receptor interaction of the methyl or isobutyl group.

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