期刊
ACS CHEMICAL NEUROSCIENCE
卷 11, 期 13, 页码 1996-2008出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00257
关键词
Hybrid compounds; multitargeted drugs; epilepsy; neuropathic pain; anticonvulsant activity; antinociceptive activity
资金
- National Science Centre, Poland [UMO-2015/18/E/NZ7/00509]
We developed a focused set of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant and antinociceptive properties. These hybrid compounds demonstrated broad-spectrum protective activity in a range of mouse models, such as the maximal electroshock (MES) test, the pentylenetetrazole-induced seizures (scPTZ), and the 6 Hz (32 mA) seizures. Compound 22 showed the most potent anticonvulsant activity (EDso MES = 23.7 mg/kg, ED50 6 Hz (32 mA) = 22.4 mg/kg, ED50 scPTZ = 59.4 mg/kg). In addition, 22 revealed potent efficacy in the formalin-induced tonic pain. These in vivo activities of 22 are likely mediated by several targets and may result from the inhibition of central sodium/calcium currents and transient receptor potential vanilloid 1 (TRPV1) receptor antagonism. Finally, the lead compound 22 revealed drug-like absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) properties in the in vitro assays, making it a potential candidate for further development in epilepsy and neuropathic pain indications.
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