Synthesis, anticonvulsant properties and 5-HT1A/5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane and [4.5]decane-1,3-dione derivatives.
A series of twenty new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives were synthesized and their anticonvulsant activity was evaluated in maximal electroshock (MES) and sc pentertazole (sc PTZ) tests. Their neurotoxicity was examined as well. Although no antiseizure properties of the investigated compounds were found in the MES model, eight of them were active in the sc PTZ test and three, namely 2-{3-[4-(2-fluorophenyl)-piperazin-1yl]-propyl}-2-aza-spiro[4.4]nonane-1,3-dione (7), 2-{3-[4-(2-fluorophenyl)-piperazin-1-yl]-propyl}-7-methyl-2-aza-spiro[4.5]-decane-1,3- dione (22) and 2-{3-[4-(3-chlorophenyl)-piperazin-1-yl]-propyl}-7-methyl-2-aza-spiro[4.5]-decane-1,3-dione (23) were classified to the Anticonvulsant Screening Program (ASP) 1 class. In addition, since the investigated compounds belong to a class of long-chain arylpiperazines, their serotonin 5-HT1A and 5-HT2A receptor affinity was determined. All the 2-OCH3 and 3-Cl derivatives were the most potent 5-HT1A receptor ligands (Ki = 24-143 and 70-107 nM, respectively), whereas the highest 5-HT2A affinity was observed for the unsubstituted and 3-Cl derivatives (Ki = 8-66 nM). No correlation between anticonvulsant and serotonergic activity was observed.
Department of Pharmaceutical Chemistry, Medical College of Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland. mfobnisk@cyf-kr.edu.pl
Jolanta
J
Obniska
Marcin
M
Kołaczkowski
Sijka
S
Charakchieva-Minol
Krystyna
K
Nedza
Małgorzata
M
Dybała
Andrzej J
AJ
Bojarski
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D051379:Mice; D010433:Pentylenetetrazole; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D010879:Piperazines; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D013141:Spiro Compounds; D010433:Pentylenetetrazole