Synthesis and benzodiazepine receptor binding of some imidazo-, pyrimido[2,1-b]benzoxazoles and pyrimido[1,2-a]benzimidazoles

A series of imidazo[2,1-b]benzoxazoles 3a-c, pyrimido[2,1-b]benzoxazoles 4-6, and pyrimido[1,2-a]benzimidazoles 7-9 was synthesized and evaluated for affinity at the benzodiazepine receptor (BZR). These compounds generally possess BZR binding affinities lower than those observed for the corresponding benzothiazole analogues. However, imidazobenzoxazole 3d possesses high binding affinity, showing an IC50 value of 77 nM. The pharmacological profile of 3d was predicted by [S-35]TBPS binding as inverse agonist whereas antagonist or partial agonist activity was suggested by the GABA ratio value. Hence, a contrasting predictive capability of GABA ratio and [S-35]TBPS binding was observed. Compound 3d should possess partial inverse agonist activity at BZR, because its [S-35]TBPS binding data is comparable to those of FG-7142.