Multitargeted Compounds Derived from (2,5-Dioxopyrrolidin-1-yl)(phenyl)-Acetamides as Candidates for Effective Anticonvulsant and Antinociceptive Agents.
Michał AbramAnna RapaczSzczepan MogilskiGniewomir LataczAnnamaria LubelskaRafał M KamińskiKrzysztof KamińskiPublished in: ACS chemical neuroscience (2020)
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 (ED50 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.
Keyphrases
- neuropathic pain
- emergency department
- anti inflammatory
- spinal cord
- spinal cord injury
- diabetic rats
- high glucose
- single cell
- mouse model
- oxidative stress
- chronic pain
- high throughput
- human health
- brain injury
- heart rate
- binding protein
- cerebral ischemia
- subarachnoid hemorrhage
- molecular docking
- risk assessment
- molecular dynamics simulations
- high intensity
- stress induced