Structure鈥揂ctivity Relationships and Molecular Modeling of 1,2,4-Triazoles as Adenosine Receptor Antagonists

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• 作者：Jens Carlsson ; Dilip K. Tosh ; Khai Phan ; Zhan-Guo Gao ; Kenneth A. Jacobson
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：3
• 期：9
• 页码：715-720
• 全文大小：340K
• 年卷期：v.3,no.9(September 13, 2012)
• ISSN：1948-5875

文摘

The structure鈥揳ctivity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A_2A adenosine receptor (hA_2AAR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA_2AAR were tested in hA₁, A_2A, and A₃ radioligand binding assays and in functional assays for the A_2BAR 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_2AAR 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_2AAR crystal structures.

Keywords:

1,2,4-Triazole; A_2A adenosine receptor; antagonist; molecular docking; structure鈭抋ctivity relationship