Li Guanguan, Stephen Michael R, Kodali Revathi, Zahn Nicolas M, Poe Michael M, Tiruveedhula V V N Phani Babu, Huber Alec T, Schussman Melissa K, Qualmann Krista, Panhans Cristina M, Raddatz Nicholas J, Baker David A, Prevot Thomas D, Banasr Mounira, Sibille Etienne, Arnold Leggy A, Cook James M
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States.
Department of Biomedical Science, Marquette University, Milwaukee, Wisconsin 53233, United States.
ARKIVOC. 2018;2018(4):158-182. doi: 10.24820/ark.5550190.p010.460. Epub 2018 Mar 11.
A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F--CH (), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reversed PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral ()-CH ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the liable ester functionality in to improve the metabolic stability, cytotoxicity, and activity as compared to . Based on the data to date, the most promising ligands are the -cyclopropyl amide GL-I-55 () and the methyl bioisostere GL-I-65 (). The metabolic stability, cytotoxicity and locomotor effects are described in this report. Based on these results, and are the most promising for further pharmacology.
合成了一系列新型咪唑并苯二氮䓬类似物，其为先导手性配体SH-053-2'F--CH（一种α2/α3/α5（Bz）GABA（A）能受体亚型选择性配体，可逆转苯环己哌啶诱导的听觉惊吓前脉冲抑制（PPI））的类似物。这些手性（）-CH配体旨在用于治疗精神分裂症和抑郁症。通过修饰中的不稳定酯官能团来设计这些新配体，以与相比提高代谢稳定性、细胞毒性和活性。根据迄今为止的数据，最有前景的配体是环丙基酰胺GL-I-55（）和甲基生物电子等排体GL-I-65（）。本报告描述了它们的代谢稳定性、细胞毒性和运动效应。基于这些结果，和在进一步的药理学研究中最具前景。
