Synthesis and Biological Evaluation of 7,8,9,10-Tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as Functionally Selective Ligands of the Benzodiazepine Receptor Site on the GABAA Receptor

Benzodiazepines are allosteric modulators of the GABAA receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABAA receptor subtypes. The α2/α3-selective partial agonist 42 exhibited potent in vivo activity.