Synthesis and dual D₂ and 5-HT_1A receptor binding affinities of 5-piperidinyl and 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones

Abstract

A series of new 5-piperidinyl and 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones have been synthesized and evaluated for dual D₂ and 5-HT_1A receptor binding affinities. The synthesized ligands are structurally related to bifeprunox, a potential atypical antipsychotic, having potent D₂ receptor antagonist and 5-HT_1A receptor agonist properties. The Suzuki–Miyaura reaction of cyclic vinyl boronate with appropriate aryl halide yielded arylpiperidine, which was eventually transformed to piperidinyl-1H-benzo[d]imidazol-2(3H)-one. The reductive amination of the latter with appropriate biarylaldehdyes rendered the synthesis of 5-piperidinyl-1H-benzo[d]imidazol-2(3H)-ones. Likewise, the Buchwald–Hartwig coupling reactions of 1-boc-piperazine with appropriate aryl halide and subsequent removal of the boc group rendered arylpiperazine. The reductive amination of the latter with appropriate biarylaldehdyes accomplished the synthesis of 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones. The structure–activity relationship studies showed that cyclopentenylpyridine and cyclopentenylbenzyl groups contribute significantly to the dual D₂ and 5-HT_1A receptor binding affinities of these compounds.

• 5-HT_1A receptor
• 5-piperidinyl-1H-benzo[d]imidazol-2(3H)-ones
• 5-piperazinyl-1H-benzo[d]imidazol-2(3H)-ones
• D₂ receptor
• schizophrenia

Acknowledgements

The facilities provided by KFUPM are sincerely acknowledged.