KA-11, a Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in Vitro Characterization

Abstract

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.

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

“…The reference AED sodium valproate (VPA) and pentylenetetrazole (PTZ) were purchased from a commercial supplier (Sigma-Aldrich, St. Louis, MO). Before in vivo and in vitro studies, AS-1 was fully characterized using the spectral ( 1 H NMR, 13 C NMR) and elemental (C, H, N) analyses. The purity and homogeneity of the compounds were assessed by thin-layer chromatography (TLC) and the gradient ultra-performance liquid chromatography (UPLC).…”

“…Spontaneous locomotor activity of mice was monitored using the IR Actimeter system supported by SedaCom32 software (Panlab/Harvard Apparatus, Barcelona, Spain) according to the method described in detail elsewhere [13].…”

“…With the aim of obtaining new and effective anticonvulsants, since many years, our efforts have been focused on the development of hybrid compounds based on the pyrrolidine-2,5dione core fragment [8][9][10][11][12][13][14]. It should be stressed that in recent years, the hybrid substances are of great importance in designing of multitargeted compounds, as they have been proven to be advantageous in the treatment of multifactorial diseases and also have been proven to alleviate health conditions linked to drug resistance [15,16].…”

“…Multitargeted compounds, proposed by our team, were designed as integrated hybrids which combine structural fragments of known and therapeutically relevant AEDs, such as ethosuximide (ETX, pyrrolidine-2,5-dione derivative), levetiracetam (LEV, pyrrolidin-2-one derivative), and lacosamide (LCS, classified as functionalized amino acid). The applied molecular hybridization yielded compounds with potent and wide anticonvulsant properties in the preclinical studies, as they were effective in the maximal electroshock (MES) seizure test, the 6-Hz (32 mA) seizure model, and the subcutaneous pentylenetetrazole (s.c. PTZ) seizure model [8][9][10][11][12][13][14]. Importantly, compounds with the aforementioned profile in the in vivo studies may be effective in the pharmacotherapy of a wide range of human epilepsies including tonic-clonic seizures (with or without secondary generalization), absence epilepsy, as well as myoclonic and partial seizures.…”

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“…Also, their biological activities were reported asanti-cancer 10 , antinociceptive 11 , antibacterial 12 , anti-tubercular 13 , anti-inflammatory 14, and neuroprotective agents 15 . The new n-mannich bases derived from pyrrolidine-2,5-dione were answerable for antiepileptic activity due to its 3methyl, 3-isopropyl and 3-benzhydryl substituent and chosen for docking studies.…”