Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides

Abstract

We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED50 MES = 49.6 mg/kg, ED50 6 Hz (32 mA) = 31.3 mg/kg, ED50scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.

New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants

“…The performed assays included PAMPA permeability, metabolic stability with use of human liver microsomes (HLMs) that were supported by the in silico studies, investigation of potential drug-drug interactions (DDIs), and safety cell-based tests. All the used protocols were described previously [ 33 , 34 , 45 , 52 , 53 , 54 ].…”

“…All assays and protocols that were used for the evaluation of compounds 53 , 60 , and 62 in the in vitro ADME-Tox studies were described previously [ 33 , 34 , 45 , 52 , 53 , 54 ]. Pre-coated PAMPA Plate System Gentest™ that was used in permeability testing was provided by Corning, (Tewksbury, MA, USA).…”

“…Furthermore, the hybrids that are described herein may be also recognized as close analogs of compound KA-104 with degraded succinimide moiety. The chemical modification of the phenylpiperazine moiety was focused mainly on the introduction of electron-withdrawing substituents that were favorable for the antiseizure effect, as it was described for succinimide derivatives previously [ 32 , 33 , 45 ]. Therefore, we hypothesize that such molecules may be characterized by a multi-targeted mechanism of action, namely, they may provide an interaction with TRPV1, Na v x, and Ca v1.2 channels, and thus may provide potent anticonvulsant and probably analgesic activity.…”

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

“…The most recent studies led to the identification of several groups of pyrrolidine-2,5-dione derivatives, characterized by potent antiseizure and antinociceptive efficacy in preclinical studies. 32 − 36 Among these substances, N -benzyl-(2,5-dioxopyrrolidin-1-yl)propanamides represented by compounds I and II shown in Figure 1 revealed especially favorable anticonvulsant and safety profiles. 28 , 29 , 37 Both compounds I and II showed antiseizure properties in commonly employed screening seizure models such as the maximal electroshock seizure test (MES), the subcutaneous pentylenetetrazol seizure test ( sc PTZ), as well as the 6 Hz seizure model (32 and 44 mA) in mice ( Table 1 ).…”

“…, anticonvulsant, antipsychotic, antidepressant, anti-inflammatory, antibacterial, antiviral, or anticancer. , Our research has been focused for many years on the development of new succinimides acting on the CNS. The most recent studies led to the identification of several groups of pyrrolidine-2,5-dione derivatives, characterized by potent antiseizure and antinociceptive efficacy in preclinical studies. − Among these substances, N -benzyl-(2,5-dioxopyrrolidin-1-yl)­propanamides represented by compounds I and II shown in Figure revealed especially favorable anticonvulsant and safety profiles. ,, Both compounds I and II showed antiseizure properties in commonly employed screening seizure models such as the maximal electroshock seizure test (MES), the subcutaneous pentylenetetrazol seizure test ( sc PTZ), as well as the 6 Hz seizure model (32 and 44 mA) in mice (Table ). They both exhibited a more potent efficacy or/and a wider spectrum of protection compared to several clinically relevant ASDs, such as ethosuximide (ETX), LEV, LCS, and especially valproic acid (VPA).…”