Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists

This study completes a series of papers devoted to the characterization of the non-competitive mGluR2/3 antagonist properties of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives with particular emphasis on derivatizations compatible with brain penetration and in vivo activity. Especially the compounds bearing a para-pyridine consistently showed in vivo activity in rat behavioral models after oral administration, for example, blockade of the mGluR2/3 agonist LY354740-induced hypoactivity and improvement of a working memory deficit induced either by LY354740 or scopolamine in the delayed match to position task (DMTP). Moreover, combination studies with a cholinesterase inhibitor show apparent synergistic effects on working memory impairment induced by scopolamine.

A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-ones was finally developed into highly drug-like non-competitive group II mGluR antagonists. After oral administration of, for example, 7am in vivo activity by reversal of the LY354740-induced hypolocomotion in rats and improvement of memory deficit in the DMTP task—also synergistically with donepezil—could be demonstrated.Figure optionsDownload as PowerPoint slide