Mechanism-based design of 2,3-benzodiazepine inhibitors for AMPA receptors

2,3-Benzodiazepine (2,3-BDZ) compounds represent a group of structurally diverse, small molecule antagonists of (R, S)-2-amino 3 (3 hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors. Antagonists of AMPA receptors are drug candidates for potential treatment of a number of neurological disorders such as epilepsy, stroke and amyotrophic lateral sclerosis (ALS). How to make better inhibitors, such as 2,3-BDZs, has been an enduring quest in drug discovery. Among a few available tools to address this specific question for making better 2,3-BDZs, perhaps the best one is to use mechanistic clues from studies of the existing antagonists to design and discover more selective and more potent antagonists. Here I review recent work in this area, and propose some ideas in the continuing effort of developing newer 2,3-BDZs for tighter control of AMPA receptor activities in vivo. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.