The library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5-dioxopyrrolidin-1-yl)propanamides and (2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed the broad spectra of activity across the preclinical seizure models, namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg). This molecule did not impair the motor coordination of animals in the chimney test even at high doses (TD50 > 1500 mg/kg), yielding superb protective indexes (PI MES > 16.97, PI PTZ > 25.04, PI 6 Hz > 71.43). As a result, 11 displayed distinctly better safety profile than clinically relevant AEDs ethosuximide, lacosamide, or valproic acid.
Recently,
compound KA-11 was identified as a promising candidate
for a new broad-spectrum anticonvulsant. This compound revealed wide
protective activity across the most important animal models of seizures
such as the maximal electroshock test (MES), the subcutaneous pentylenetetrazole
test (scPTZ), and the six-hertz test (6 Hz, 32 mA).
Importantly, KA-11 was devoid of acute neurological activity, which
was assessed by applying the chimney test (TD50 value higher
than 1500 mg/kg). The preliminary in vivo results confirmed favorable
anticonvulsant and safety properties of KA-11. With the aim of further
biological characterization of KA-11, in the current studies we evaluated
its antiepileptogenic activity in the kindling model of epilepsy induced
by repeated injection of PTZ in mice. Furthermore, we assessed the
antinociceptive activity of KA-11 in several animal pain models. As
a result, KA-11 (at all doses applied: 25, 50, and 100 mg/kg) significantly
delayed the progression of kindling induced by repeated injection
of PTZ in mice. Additionally, KA-11 revealed potent antinociceptive
activity in the formalin-induced tonic pain and, importantly, in the
oxaliplatin-induced neuropathic pain model in mice. Moreover, KA-11
did not induce motor deficits in the rotarod test. Patch-clamp experiments
revealed that one of the mechanisms of action of KA-11 is inhibition
of voltage-gated sodium currents. Compound KA-11 appeared to be safe in relation to hepatotoxic
properties as no phospholipidosis induction was determined in HepG2
cells at 50 μM, and a small, statistically significant decrease
of cell viability was observed only at the highest used dose of 100
μM. Moreover, KA-11 did not affect the function of CYP2D6. The
aforementioned hybrid substance proved to penetrate the biological
membranes in the in vitro permeability assays.
Since the year 1993, when 5-HT receptor (5-HT R) was discovered, there is no selective 5-HT R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5-HT R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by "drug-likeness" estimation of the first series of selective and potent 5-HT R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives (11-16). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2. The experiments showed promising drug-like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13. The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant-like activity in the FST. Taking into account the beneficial properties of 13, i.e., good drug-like parameters, the significant antagonistic action, high selectivity to 5-HT R, and its in vivo antidepressant-like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5-HT receptor.
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.
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