期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 3, 期 9, 页码 715-720出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml300097g
关键词
1,2,4-Triazole; A(2A) adenosine receptor; antagonist; molecular docking; structure-activity relationship
资金
- NIDDK Intramural Res. Program
- Knut and Alice Wallenberg Foundation
The structure-activity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A(2A) adenosine receptor (hA(2A)AR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA(2A)AR were tested in hA(1), A(2A), and A(3) radioligand binding assays and in functional assays for the A(2B)AR subtype. As a series of closely related analogs of the initial lead, 1, did not display improved binding affinity or selectivity, molecular docking was used to guide the selection of more distantly related molecules. This resulted in the discovery of 32, a hA(2A)AR antagonist (K-i 200 nM) with high ligand efficiency. In light of the SAR for the 1,2,4-triazole scaffold, we also investigated the binding mode of these compounds based on docking to several A(2A)AR crystal structures.
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