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Rational approaches for the design of various GABA modulators and their clinical progression
Molecular Diversity ( IF 3.8 ) Pub Date : 2020-03-13 , DOI: 10.1007/s11030-020-10068-4
Kavita Bhagat 1 , Jatinder V Singh 1 , Piyusha P Pagare 2 , Nitish Kumar 1 , Anchal Sharma 1 , Gurinder Kaur 1 , Nihar Kinarivala 3 , Srinivasa Gandu 4 , Harbinder Singh 1 , Sahil Sharma 1, 3 , Preet Mohinder S Bedi 1
Affiliation  

Abstract

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer’s disease, Huntington’s chorea, migraine, Parkinson’s disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure–activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.

Graphic abstract



中文翻译:

各种 GABA 调节剂的合理设计方法及其临床进展

摘要

GABA(γ-氨基丁酸)是中枢神经系统中重要的抑制性神经递质。GABA能神经传递的减弱在多种神经系统疾病的病因学中起着重要作用,包括癫痫、阿尔茨海默病、亨廷顿舞蹈病、偏头痛、帕金森病、神经性疼痛和抑郁症。GABA能活性的增加可以通过直接激动GABA A受体、抑制GABA的酶促分解或通过抑制GABA转运蛋白(GAT)来实现。这些功能使 GABA 受体调节剂和 GAT 成为治疗与 GABA 活性降低相关的脑部疾病的有吸引力的药物靶标。在过去的十年里,已经有一些关于 GABA 调节剂(GABA 受体、GABA 转运蛋白和 GABA 酶抑制剂)开发的报道。因此,本综述的重点是概述开发 GABA 调节剂的各种设计策略和合成方法。此外,还讨论了生物活性衍生物的机理见解、结构-活性关系和分子建模输入。还总结了过去几年在 GABA 受体调节剂的临床转化和开发方面取得的进展。该汇编将引起神经科学领域研究人员的极大兴趣。根据详细的文献,可以得出结论,许多分子已经显示出显着的结果及其有希望的潜力,显然使它们成为未来潜在的候选药物。

图文摘要

更新日期:2020-04-13
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