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Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-15 , DOI: 10.1021/acschemneuro.0c00255
Adi Lahiani 1 , Dikla Haham-Geula 1 , David Lankri 2 , Susan Cornell-Kennon 3 , Erik M Schaefer 3 , Dmitry Tsvelikhovsky 2 , Philip Lazarovici 1
Affiliation  

Polyneuropathy is a disease involving multiple peripheral nerves injuries. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery and therefore, regulation of neurite outgrowth might be a candidate for treating polyneuropathies. In a recent study, we synthesized and established the methylene-cycloalkylacetate (MCAs) pharmacophore as a lead for the development of a neurotropic drug (inducing neurite/axonal outgrowth) using the PC12 neuronal model. In the present study we extended the characterizations of the in vitro neurotropic effect of the derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid (MCA-13) on dorsal root ganglia and spinal cord neuronal cultures and analyzed its safety properties using blood biochemistry and cell counting, acute toxicity evaluation in mice and different in vitro “off-target” pharmacological evaluations. This MCA derivative deserves further preclinical mechanistic pharmacological characterizations including therapeutic efficacy in in vivo animal models of polyneuropathies, toward development of a clinically relevant neurotropic drug.

中文翻译:


亚甲基环烷基乙酸酯 (MCA) 衍生物 3-(3-烯丙基-2-亚甲基环己基) 丙酸的神经活性和安全性。



多发性神经病是一种涉及多处周围神经损伤的疾病。轴突再生仍然是可塑性、再生、回路形成和最终功能恢复的主要先决条件,因此,神经突生长的调节可能是治疗多发性神经病的候选者。在最近的一项研究中,我们使用 PC12 神经元模型合成并建立了亚甲基环烷基乙酸酯 (MCAs) 药效团,作为开发神经营养药物(诱导神经突/轴突生长)的先导。在本研究中,我们扩展了衍生物 3-(3-烯丙基-2-亚甲基环己基) 丙酸 (MCA-13) 对背根神经节和脊髓神经元培养物的体外神经营养作用的特征,并使用以下方法分析了其安全特性:血液生化和细胞计数、小鼠急性毒性评估以及不同的体外“脱靶”药理学评估。这种 MCA 衍生物值得进一步的临床前机制药理学表征,包括在体内多发性神经病动物模型中的治疗功效,以开发临床相关的神经营养药物。
更新日期:2020-09-02
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