Selectivity and Anti-Parkinson鈥檚 Potential of Thiadiazolidinone RGS4 Inhibitors

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• 作者：Levi L. Blazer ; Andrew J. Storaska ; Emily M. Jutkiewicz ; Emma M. Turner ; Mariangela Calcagno ; Susan M. Wade ; Qin Wang ; Xi-Ping Huang ; John R. Traynor ; Stephen M. Husbands ; Michele Morari ; Richard R. Neubig
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：June 17, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：911-919
• 全文大小：442K
• ISSN：1948-7193

文摘

Many current therapies target G protein coupled receptors (GPCR), transporters, or ion channels. In addition to directly targeting these proteins, disrupting the protein鈥損rotein interactions that localize or regulate their function could enhance selectivity and provide unique pharmacologic actions. Regulators of G protein signaling (RGS) proteins, especially RGS4, play significant roles in epilepsy and Parkinson鈥檚 disease. Thiadiazolidinone (TDZD) inhibitors of RGS4 are nanomolar potency blockers of the biochemical actions of RGS4 in vitro. Here, we demonstrate the substantial selectivity (8- to >5000-fold) of CCG-203769 for RGS4 over other RGS proteins. It is also 300-fold selective for RGS4 over GSK-3尾, another target of this class of chemical scaffolds. It does not inhibit the cysteine protease papain at 100 渭M. CCG-203769 enhances G伪_q-dependent cellular Ca²⁺ signaling in an RGS4-dependent manner. TDZD inhibitors also enhance G伪_i-dependent 未-OR inhibition of cAMP production in SH-SY-5Y cells, which express endogenous receptors and RGS4. Importantly, CCG-203769 potentiates the known RGS4 mechanism of G伪_i-dependent muscarinic bradycardia in vivo. Furthermore, it reverses raclopride-induced akinesia and bradykinesia in mice, a model of some aspects of the movement disorder in Parkinson鈥檚 disease. A broad assessment of compound effects revealed minimal off-target effects at concentrations necessary for cellular RGS4 inhibition. These results expand our understanding of the mechanism and specificity of TDZD RGS inhibitors and support the potential for therapeutic targeting of RGS proteins in Parkinson鈥檚 disease and other neural disorders.