TY - JOUR
T1 - 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
AU - Ballet, Steven
AU - Feytens, Debby
AU - Buysse, Koen
AU - Chung, Nga N.
AU - Lemieux, Carole
AU - Tumati, Suneeta
AU - Keresztes, Attila
AU - Van Duppen, Joost
AU - Lai, Josephine
AU - Varga, Eva
AU - Porreca, Frank
AU - Schiller, Peter W.
AU - Vanden Broeck, Jozef
AU - Tourwé, Dirk
PY - 2011/4/14
Y1 - 2011/4/14
N2 - 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.
AB - 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.
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U2 - 10.1021/jm1016285
DO - 10.1021/jm1016285
M3 - Article
C2 - 21413804
AN - SCOPUS:79953777227
SN - 0022-2623
VL - 54
SP - 2467
EP - 2476
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -