title: 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.
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'-(CF(3))(2)-Bn], 20 [Ac-Aba-Gly-NMe-3',5'-(CF(3))(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'-(CF(3))(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'-(CF(3))(2)-Bn], which combines the N terminus of the established Dmt(1)-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH(2)) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, that is, Dmt-D-Arg-Aba-Gly-NH(2) (36), also proved to be an extremely potent and balanced μ and δ opioid receptor agonist with subnanomolar binding and in vitro functional activity.
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium. sballet@vub.ac.be
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
authors.forename: Debby
authors.initials: D
authors.lastname: Feytens
authors.forename: Koen
authors.initials: K
authors.lastname: Buysse
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.forename: Carole
authors.initials: C
authors.lastname: Lemieux
authors.forename: Suneeta
authors.initials: S
authors.lastname: Tumati
authors.forename: Attila
authors.initials: A
authors.lastname: Keresztes
authors.forename: Joost
authors.initials: J
authors.lastname: Van Duppen
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Eva
authors.initials: E
authors.lastname: Varga
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.forename: Jozef
authors.initials: J
authors.lastname: Vanden Broeck
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
mesh_terms: D024322:Amino Acids, Aromatic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D024322:Amino Acids, Aromatic; D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D011957:Receptors, Opioid