Pandey Kamal P, Khan Zubair Ahmed, Golani Lalit K, Mondal Prithu, Mian Yeunus, Rashid Farjana, Tiruveedhula V V N Phani Babu, Knutson Daniel E, Sharmin Dishary, Ahmed Taukir, Rezvanian Sepideh, Zahn Nicolas M, Arnold Leggy A, Witkin Jeffrey M, Cook James M
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA.
ARKIVOC. 2020;2020(Pt 7):242-256. doi: 10.24820/ark.5550190.p011.398. Epub 2020 Dec 2.
Antinociceptive ligand HZ-166 is a GABA α2/α3 receptor subtype-selective potentiator. It has been shown to exhibit anxiolytic-like effects in rodent and rhesus monkeys, as well as reduced sedative/ataxic liabilities. In order to improve the metabolic stability of HZ-166, the ethyl ester moiety was bioisosterically replaced with 2,4-disubstituted oxazoles and oxazolines. The new analogs of HZ-166 were synthesized, characterized, and evalutated for their biological activity and docked in the human full-length heteromeric α1β3γ2L GABA receptor subtype CyroEM structure (6HUO). Importantly no sedation nor ataxia was observed on the rotorod for LKG-I-70 () or KPP-III-51 () at 100 and 120 mg/kg, respectively. These was also no loss of righting response for either ligand.
抗伤害感受配体HZ-166是一种GABAα2/α3受体亚型选择性增强剂。已证明它在啮齿动物和恒河猴中表现出抗焦虑样作用，以及降低的镇静/共济失调副作用。为了提高HZ-166的代谢稳定性，乙酯部分被2,4-二取代恶唑和恶唑啉进行生物电子等排体取代。合成并表征了HZ-166的新类似物，并评估了它们的生物活性，并将其对接至人全长异源三聚体α1β3γ2L GABA受体亚型的冷冻电镜结构（6HUO）中。重要的是，在转棒实验中，分别给予100和120mg/kg的LKG-I-70（）或KPP-III-51（）时，未观察到镇静或共济失调。这两种配体也均未出现翻正反射消失的情况。
