Synthesis, anticonvulsant activity and 5-HT1A/5-HT7 receptors affinity of 1-[(4-arylpiperazin-1-yl)-propyl]-succinimides

Abstract

BackgroundEpilepsy is the most prevalent neurological disorder, affecting approximately 50 million people worldwide. Even though significant advances have been made in epilepsy research, convulsions in about 30% of epileptics are still inadequately controlled by standard drug therapy. For this reason, constant attempts are made to investigate new chemical agents and mechanisms through which epilepsy can be effectively controlled. Therefore, in the present studies, a series of sixteen new 1-[(4-arylpiperazin-1-yl)-propyl]-3-methyl-3-phenyl- and 3-ethyl-3-methylpyrrolidine-2,5-dione derivatives as potential anticonvulsant agents was synthesized. MethodsAnticonvulsant properties were evaluated in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and psychomotor seizure (6-Hz) tests after intraperitoneal injection in mice. The acute neurological toxicity was determined in the motor impairment rotorod screen. ResultsThe compounds showed activity at a dose of 30mg/kg (4, 8, 16) or 100mg/kg (6, 9, 10, 12, 17, 18) in the MES model in mice. Four or them (8, 10, 16, 17) were also evaluated after po administration in rats. In this series, the most active was 1-{3-[4-(3-chlorophenyl)-piperazin-1-yl]-propyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8) with the ED50 value of 28.2mg/kg, TD50 value of 268.5mg/kg and protective index of 9.52 after po administration in rats. ConclusionsTaking into consideration the role of 5-HT1A and 5-HT7 receptor subtypes in relation to the control of seizures as well as the fact that all compounds obtained belong to the class of long-chain arylpiperazines, their serotonin 5-HT1A and 5-HT7 receptor affinity was determined. The most potent 5-HT1A receptor ligands are 2-OCH3 (11, 19) and 3-Cl (8, 16) derivatives with Ki = 72, 14nM, and 109, 44nM, respectively. With respect to the 5-HT7 receptors, the best Ki values were obtained for derivatives 8 and 11 (Ki = 76nM and 63 nM, respectively).