Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 781, Issue -, Pages 239-249Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2016.04.033
Keywords
Anticonvulsant activity; Formalin; Oxaliplatin; Motor coordination; Ion channel binding; Pyrrolidine-2; 5-dione
Categories
Funding
- National Science Centre [DEC-2013/11/B/N27/02081]
- Funds for Statutory Activity of Jagiellonian University Medical College, Krakow, Poland [K/ZDS/005545, K/ZDS/005537]
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The aim of the present experiments was to examine the anticonvulsant and antinociceptive activity of five new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in animal models of seizures and pain. The antiseizure activity was investigated in three acute models of seizures, namely, the maximal electroshock (MES), the subcutaneous pentylenetetrazole (scPTZ), and 6 Hz psychomotor seizure tests in mice. The antinociceptive properties were estimated in the formalin model of tonic pain, and in the oxaliplatin-induced neuropathic pain model in mice. Considering drug safety evaluation, acute neurological toxicity was determined in the rotarod test. Three tested compounds (3,4, and 7) displayed a broad spectrum of anticonvulsant activity and showed better protective indices than those obtained for MES/scPTZ/6 Hz active reference drug - valproic acid. Furthermore, three compounds (3, 4, and 6) demonstrated a significant antinociceptive effect in the formalin test, as well as antiallodynic activity in the oxaliplatin-induced neuropathic pain model. Among the tested agents, compounds 3 and 4 displayed not only antiseizure properties, but also collateral prominent analgesic properties. The in vitro binding study indicated that the plausible mechanism of action of chosen compound (4) was the influence on neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. (C) 2016 Elsevier B.V. All rights reserved.
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