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.
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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DOI：
10.1021/jm1016285
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发表时间：
2011-04-14
影响因子：
7.3
通讯作者：
Tourwe, Dirk
中科院分区：
文献类型：
--
作者：
Ballet, Steven;Feytens, Debby;Buysse, Koen;Chung, Nga N.;Lemieux, Carole;Tumati, Suneeta;Keresztes, Attila;Van Duppen, Joost;Lai, Josephine;Varga, Eva;Porreca, Frank;Schiller, Peter W.;Broeck, Jozef Vanden;Tourwe, Dirk
通过筛选构象受限的芳香族氨基酸作为新的NK1受体拮抗剂的碱基，发现了3个新的NK1受体拮抗剂，19个[Ac-Aba-Gly-NH-3‘，5’-(CF3)2-Bn]，20个[Ac-Aba-Gly-NME-3‘，5’-(CF3)2-Bn]和23个[Ac-Tic-NME-3‘，5’-(CF3)2-Bn]，它们能对抗NK1R的内源性配体P物质的兴奋作用。该系列中最活跃的NK1拮抗剂20[Ac-Aba-Gly-NME-3‘，5’-(CF3)2-Bn]被用来设计一种新型的、有效的嵌合阿片激动剂-NK1受体拮抗剂35[DMT-D-Arg-Aba-Gly-NME-3‘，5’-(CF3)2-Bn]，它结合了已建立的DMT1-DALDA激动剂阿片药效团(H-DMT-D-Arg-Phe-Lys-NH2)和20，NK1R配体。嵌合化合物35的阿片成分，即DMT-D-Arg-Aba-Gly-NH2 36，也被证明是一种非常有效和平衡的μ和δ阿片受体激动剂，具有亚纳米分子结合和体外功能活性。
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′-(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′,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, i.e. 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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影响因子：
2.7
作者：
Ballet, Steven;Feytens, Debby;Balboni, Gianfranco
通讯作者：
Balboni, Gianfranco
影响因子：
7.3
作者：
Feytens, Debby;De Vlaeminck, Magali;Reubi, Jean Claude
通讯作者：
Reubi, Jean Claude
影响因子：
--
作者：
Janecka, A;Poels, J;Vanden Broeck, J
通讯作者：
Vanden Broeck, J
DOI：
10.1111/j.1399-3011.2005.00291.x
发表时间：
2005-11-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Ballet, S;Frycia, A;Tourwé, D
通讯作者：
Tourwé, D
影响因子：
2.1
作者：
Ballet, S.;De Wachter, R.;Tourwe, D.
通讯作者：
Tourwe, D.