Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist

Steven Ballet, Debby Feytens, Koen Buysse, Nga N. Chung, Carole Lemieux, Suneeta Tumati, Attila Keresztes, Joost Van Duppen, Josephine Lai, Eva Varga, Frank Porreca, Peter W. Schiller, Jozef Vanden Broeck, Dirk Tourwé

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3′, 5′-(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3′,5′- (CF3)2-Bn], and 23 [Ac-Tic-NMe-3′,5′-(CF 3)2-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R. The most active NK1 antagonist of the series, 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3) 2-Bn], was then used in the design of a novel, potent chimeric opioid agonist-NK1 receptor antagonist, 35 [Dmt-d-Arg-Aba-Gly-NMe-3′,5′- (CF3)2-Bn], which combines the N terminus of the established Dmt1-DALDA agonist opioid pharmacophore (H-Dmt-d-Arg-Phe-Lys-NH2) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, that is, Dmt-d-Arg-Aba-Gly-NH2 (36), also proved to be an extremely potent and balanced μ and δ opioid receptor agonist with subnanomolar binding and in vitro functional activity.

Original languageEnglish (US)
Pages (from-to)2467-2476
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
StatePublished - Apr 14 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Ballet, S., Feytens, D., Buysse, K., Chung, N. N., Lemieux, C., Tumati, S., Keresztes, A., Van Duppen, J., Lai, J., Varga, E., Porreca, F., Schiller, P. W., Vanden Broeck, J., & Tourwé, D. (2011). Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist. Journal of Medicinal Chemistry, 54(7), 2467-2476. https://doi.org/10.1021/jm1016285