Synthesis, anticonvulsant, and antinociceptive activity of new 3‐(3‐methyl‐2, 5‐dioxo‐3‐phenylpyrrolidin‐1‐yl)propanamides and 3‐phenyl‐butanamides. Issue 1 (16th September 2020)

• Record Type: Journal Article
• Authors: Obniska, Jolanta; Góra, Małgorzata; Rapacz, Anna; Sałat, Kinga; Rybka, Sabina; Abram, Michał; Jakubiec, Marcin; Kamiński, Krzysztof
• Is Part Of: Archiv der Pharmazie. Volume 354:Issue 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-09-16
• Subjects: amides -- anticonvulsant activity -- antinociceptive activity -- epilepsy -- imides -- in vitro studies -- in vivo studies -- neuropathic pain; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202000225
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: A focused library of new 3‐(3‐methyl‐2, 5‐dioxo‐3‐phenylpyrrolidin‐1‐yl)propanamides and their nonimide analogs were synthesized and tested for anticonvulsant activity. These compounds were obtained through the coupling reaction of the starting carboxylic acids with appropriate amines. The initial anticonvulsant screening was performed in mice (intraperitoneal administration) using the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models. The most promising compound 6 showed more potent protection in the MES and scPTZ tests than valproic acid, which is still recognized as one of the most relevant first‐line anticonvulsants. The structure–activity relationship analysis revealed that the presence of the pyrrolidine‐2, 5‐dione ring is important but not indispensable to retain anticonvulsant activity. Additionally, compound 6 showed potent antinociceptive properties in the oxaliplatin‐induced neuropathic pain model in mice. The most plausible mechanism of action for compound 6 may result from its influence on the neuronal sodium channel (Site 2) and the high‐voltage‐activated L‐type calcium channel. Abstract : New 3‐(3‐methyl‐2, 5‐dioxo‐3‐phenylpyrrolidin‐1‐yl)propanamides and their nonimide analogs were synthesized and tested for anticonvulsant activity. Compound 6 showed more potent protection in the maximal electroshock seizure and subcutaneous pentylenetetrazole seizure models than valproic acid. Morover, 6 revealed potent antinociceptive properties in the oxaliplatin‐induced neuropathic pain model in mice. It interacts with the neuronal sodium channel (Site 2) and the high‐voltage‐activated L‐type calcium channel.