Design and development of 1, 3, 5-triazine-thiadiazole hybrids as potent adenosine A2A receptor (A2AR) antagonist for benefit in Parkinson's disease. (14th September 2020)

• Record Type: Journal Article
• Authors: Masih, Anup; Singh, Saumya; Agnihotri, Amol Kumar; Giri, Sabeena; Shrivastava, Jitendra Kumar; Pandey, Nidhi; Bhat, Hans Raj; Singh, Udaya Pratap
• Is Part Of: Neuroscience letters. Volume 735(2020)
• Publication Date: 2020-09-14
• Subjects: Parkinson's disease -- Adenosine A2A receptor -- 1, 3, 5-triazine -- Antagonist -- Docking; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2020.135222
• Languages: English
• ISSNs: 0304-3940

Abstract

Graphical abstract: Highlights: Discovery of 1, 3, 5-triazine-thiadiazole as novel A2 A receptor antagonist. Compound 7e as most potent A2 A receptor antagonist. Compound 7e found deeply buried into the active site of A2 A receptor. Abstract: Various studies showed adenosine A2 A receptors (A2 ARs) antagonists have profound therapeutic efficacy in Parkinsons Disease (PD) by improving dopamine transmission, thus being active in reversing motor deficits and extrapyramidal symptoms related to the disease. Therefore, in the presents study, we have showed the development of novel 1, 3, 5-triazine-thiadiazole derivative as potent A2 ARs antagonist. In the radioligand binding assay, these molecules showed excellent binding affinity with A2 AR compared to A1 R, with significant selectivity. Results suggest, compound 7e as most potent antagonist of A2 AR among the tested series. In docking analysis with A2 AR protein model, compound 7e found to be deeply buried into the cavity of receptor lined via making numerous interatomic contacts with His264, Tyr271, His278, Glu169, Ala63, Val84, Ile274, Met270, Phe169. Collectively, our study demonstrated 1, 3, 5-triazine-thiadiazole hybrid as a highly effective scaffold for the design of new A2 A antagonists.