Synthesis and evaluation of novel tricyclic benzo[4.5]cyclohepta[1.2]pyridine derivatives as NMDA/NR2B antagonists

A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure–activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K+ channel. Preferred compounds were subsequently evaluated for selectivity in an α1-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.

Graphical abstractA novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Compound (−)23b was identified as one which showed good separation of NR2B and hERG activities.Figure optionsDownload full-size imageDownload as PowerPoint slide