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


METHODS
Anticonvulsant 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.


RESULTS
The compounds showed activity at a dose of 30 mg/kg (4, 8, 16) or 100 mg/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 ED(50) value of 28.2 mg/kg, TD(50) value of 268.5 mg/kg and protective index of 9.52 after po administration in rats.


CONCLUSIONS
Taking into consideration the role of 5-HT(1A) and 5-HT(7) 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-HT(1A) and 5-HT(7) receptor affinity was determined. The most potent 5-HT(1A) receptor ligands are 2-OCH(3) (11, 19) and 3-Cl (8, 16) derivatives with K(i) = 72, 14 nM, and 109, 44 nM, respectively. With respect to the 5-HT(7) receptors, the best K(i) values were obtained for derivatives 8 and 11 (K(i) = 76 nM and 63 nM, respectively).
Department of Medicinal Chemistry, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland. mfobnisk@cyf-kr.edu.pl
Jolanta
J
Obniska
Iwona
I
Chlebek
Krzysztof
K
Kamiński
Andrzej J
AJ
Bojarski
Grzegorz
G
Satała
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism; D013388:Succinimides / Q000138:chemical synthesis / Q000737:chemistry
D000927:Anticonvulsants; D010879:Piperazines; D011985:Receptors, Serotonin; D013388:Succinimides; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A