Analgesic, anticonvulsant and antioxidant activities of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride in mice.
Recently we have shown that 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride (LPP1) is an antinociceptive and local anesthetic agent in rodents. Below an extended study of the pharmacological activity of LPP1 is described. In vitro LPP1 has no affinity for GABA(A), opioidergic μ and serotonergic 5-HT(1A) receptors. The total antioxidant capacity of LPP1 (1-10mM) measured as ABTS radical cation-scavenging activity showed that LPP1 has dose-dependent antioxidant properties in vitro. Low plasma concentration of this compound detected by means of HPLC method 30min after its intraperitoneal administration suggests a rapid conversion to metabolite(s) which may be responsible for its analgesic and anticonvulsant activities in vivo. In vivo the compound's influence on the electroconvulsive threshold and its activity in the maximal electroshock seizure test (MES) were evaluated. The results demonstrated that LPP1 had an anticonvulsant activity in the MES model (ED(50)=112mg/kg) and at a dose of 50mg/kg was able to elevate the electroconvulsive threshold for 8mA as compared to the vehicle-treated mice. The analgesic activity of LPP1 was investigated in the acetic acid-induced writhing test in two groups of mice: animals with sensory C-fibers ablated, and mice with C-fibers unimpaired. It proved the potent activity of this compound in both groups (approximately 85% as compared to the vehicle-treated mice). The adverse effects of LPP1 were evaluated as acute toxicity (LD(50)=747.8mg/kg) and motor coordination impairments in the rotarod and chimney tests. The results from these tests show that LPP1 at doses higher than 100mg/kg is likely to impair the motor performance of experimental animals. Concluding, LPP1 is an analgesic and anticonvulsant compound which has antioxidant properties in vitro. Further studies are necessary to assess whether the antioxidant activity and the receptor profiling demonstrated in vitro can be confirmed for its metabolite(s) that are formed in vivo.
Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. salat.kinga@gmail.com
Kinga
K
Salat
Andrzej
A
Moniczewski
Robert
R
Salat
Monika
M
Janaszek
Barbara
B
Filipek
Barbara
B
Malawska
Krzysztof
K
Wieckowski
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D000700:Analgesics; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants; D000975:Antioxidants; D052160:Benzothiazoles / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004597:Electroshock; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004856:Postural Balance / Q000187:drug effects; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013451:Sulfonic Acids / Q000378:metabolism
C547282:3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)dihydrofuran-2-one; D000700:Analgesics; D000927:Anticonvulsants; D000975:Antioxidants; D052160:Benzothiazoles; D016166:Free Radical Scavengers; D005609:Free Radicals; D010879:Piperazines; D011963:Receptors, GABA-A; D017450:Receptors, Opioid, mu; D013451:Sulfonic Acids; D044282:Receptor, Serotonin, 5-HT1A; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; D015107:4-Butyrolactone; D002211:Capsaicin