Synthesis, Pharmacology, and Structure−Activity Relationships of Novel Imidazolones and Pyrrolones as Modulators of GABAAReceptors

Abstract

New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABA_A receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED₅₀ of 27.4 and 12.8 mg/kg and TD₅₀ (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure−activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABA_A mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.