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
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- 作者：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 Tourwe虂
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：April 14, 2011
- 年：2011
- 卷：54
- 期：7
- 页码：2467-2476
- 全文大小：987K
- 年卷期：v.54,no.7(April 14, 2011)
- ISSN：1520-4804
文摘
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鈥?5鈥?(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3鈥?5鈥?(CF3)2-Bn], and 23 [Ac-Tic-NMe-3鈥?5鈥?(CF3)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鈥?5鈥?(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鈥?5鈥?(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 渭 and 未 opioid receptor agonist with subnanomolar binding and in vitro functional activity.