Ligand Based Approach to L-Type Calcium Channel by Imidazo[2,1-b]thiazole-1,4-Dihydropyridines: from Heart Activity to Brain Affinity

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• 作者：Alessandra Locatelli ; Sandro Cosconati ; Matteo Micucci ; Alberto Leoni ; Luciana Marinelli ; Andrea Bedini ; Pierfranco Ioan ; Santi Mario Spampinato ; Ettore Novellino ; Alberto Chiarini ; Roberta Budriesi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：3866-3877
• 全文大小：467K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

The synthesis, characterization, and functional in vitro assay in cardiac and smooth muscle (vascular and nonvascular) of a series of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines are reported. To define the calcium blocker nature of the imidazo[2,1-b]thiazole-1,4-DHPs and their selectivity on Ca_v1.2 and Ca_v1.3 isoforms, we performed binding studies on guinea pig atrial and ventricular membranes on intact cells expressing the cloned Ca_v1.2a subunit and on rat brain cortex. To get major insights into the reasons for the affinity for Ca_v1.2 and/or Ca_v1.3, molecular modeling studies were also undertaken. Some physicochemical and pharmacokinetic properties of selected compounds were calculated and compared. All the biological data collected and reported herein allowed us to rationalize the structure鈥揳ctivity relationship of the 4-imidazo[2,1-b]thiazole-1,4-DHPs and to identify which of these enhanced the activity at the central level.