期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 7, 页码 2467-2476出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm1016285
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资金
- Research Foundation-Flanders (F.W.O.) [G.0008.08]
- Institute for Innovation through Science and Technology (IWT Vlaanderen
- MDEIE
- NIH [DA-25196]
- CIHR [MOP-89716]
- Interuniversity Attraction Poles program [P6/14]
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 mu and delta opioid receptor agonist with subnanomolar binding and in vitro functional activity.
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