He Xinhua, Lakkaraju Sirish K, Hanscom Marie, Zhao Zaorui, Wu Junfang, Stoica Bogdan, MacKerell Alexander D, Faden Alan I, Xue Fengtian
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States.
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Bioorg Med Chem. 2015 May 1;23(9):2211-20. doi: 10.1016/j.bmc.2015.02.054. Epub 2015 Mar 6.
Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for treating traumatic brain injury (TBI). Using computational and medicinal methods, the structure-activity relationship of a class of acyl-2-aminobenzimidazoles (1-26) is reported. The new compounds are designed based on the chemical structure of 3,3'-difluorobenzaldazine (DFB), a known mGluR5 PAM. Ligand design and prediction of binding affinities of the new compounds have been performed using the site identification by ligand competitive saturation (SILCS) method. Binding affinities of the compounds to the transmembrane domain of mGluR5 have been evaluated using nitric oxide (NO) production assay, while the safety of the compounds is tested. One new compound found in this study, compound 22, showed promising activity with an IC₅₀ value of 6.4 μM, which is ∼20 fold more potent than that of DFB. Compound 22 represents a new lead for possible development as a treatment for TBI and related neurodegenerative conditions.
代谢型谷氨酸受体5(mGluR5)的正变构调节剂(PAM)是治疗创伤性脑损伤(TBI)的有前景的治疗药物。运用计算和药物方法,报道了一类酰基-2-氨基苯并咪唑(1-26)的构效关系。新化合物基于已知的mGluR5 PAM 3,3'-二氟苯甲醛腙(DFB)的化学结构设计。使用配体竞争饱和位点识别(SILCS)方法进行了新化合物的配体设计和结合亲和力预测。使用一氧化氮(NO)生成测定法评估了化合物与mGluR5跨膜结构域的结合亲和力,同时测试了化合物的安全性。本研究中发现的一种新化合物,即化合物22,显示出有前景的活性,IC₅₀值为6.4 μM,比DFB的效力高约20倍。化合物22代表了一种可能作为TBI及相关神经退行性疾病治疗药物开发的新先导物。