Remya Chandran, Dileep K V, Koti Reddy Eeda, Mantosh Kumar, Lakshmi Kesavan, Sarah Jacob Reena, Sajith Ayyiliyath M, Jayadevi Variyar E, Anwar Shaik, Zhang Kam Y J, Sadasivan C, Omkumar R V
Department of Biotechnology and Microbiology, Kannur University, Dr. Janaki Ammal Campus, Thalassery, Kerala 670661, India.
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
Comput Struct Biotechnol J. 2021 Aug 3;19:4517-4537. doi: 10.1016/j.csbj.2021.07.041. eCollection 2021.
The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer's disease (AD). Tacrine, a potent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepatotoxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed structure-based modifications on tacrine, chemical synthesis of the derivatives and validation of their activities. Nineteen such derivatives showed inhibition with values in the range of 18.53 ± 2.09 - 184.09 ± 19.23 nM against AChE and 0.27 ± 0.05 - 38.84 ± 9.64 μM against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activitiy against butyrylcholinesterase. MTDL-201 was also devoid of hepatotoxicity . Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs among which 201 appears to be a potential candidate for immediate preclinical evaluations.
神经精神疾病复杂的多因素性质需要能够干预疾病进展背后各种亚病理状态的多靶点药物。用小分子靶向胆碱能和谷氨酸能神经传递中的损伤已被认为是阿尔茨海默病（AD）潜在的疾病修饰方法之一。他克林是一种有效的乙酰胆碱酯酶（AChE）抑制剂，是首个被美国食品药品监督管理局（FDA）批准用于治疗AD的药物。他克林也是N-甲基-D-天冬氨酸受体（NMDAR）的低亲和力拮抗剂。然而，由于其肝毒性，他克林后来被撤出临床使用。为了开发针对AChE和NMDAR的新型高亲和力多靶点导向配体（MTDL），并降低肝毒性，我们对他克林进行了基于结构的修饰、衍生物的化学合成及其活性验证。19种此类衍生物对AChE的抑制值在18.53±2.09 - 184.09±19.23 nM范围内，对NMDAR的抑制值在0.27±0.05 - 38.84±9.64 μM范围内。一些选定的化合物还保护大鼠原代皮层神经元免受谷氨酸诱导的兴奋性毒性。两种他克林衍生的MTDL，即201和208，通过预防兴奋性毒性剂谷氨酸给药诱导的行为损伤，在大鼠中显示出疗效。此外，这些合成化合物中的几种对丁酰胆碱酯酶也表现出有前景的抑制活性。MTDL-201也没有肝毒性。鉴于MTDL在疾病修饰治疗中的治疗潜力，我们的研究揭示了几种有前景的MTDL，其中201似乎是立即进行临床前评估的潜在候选药物。
