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Papers: 11 May 2024 - 17 May 2024

2024 May 14

ACS Chem Neurosci


Novel Alaninamide Derivatives with Drug-like Potential for Development as Antiseizure and Antinociceptive Therapies─In Vitro and In Vivo Characterization.


Jakubiec M, Abram M, Zagaja M, Andres-Mach M, Szala-Rycaj J, Latacz G, Honkisz-Orzechowska E, Mogilski S, Kubacka M, Szafarz M, Pociecha K, Przejczowska-Pomierny K, Wyska E, Socała K, Nieoczym D, Szulczyk B, Wlaź P, Metcalf CS, Wilcox K, Kamiński RM, Kamiński K


In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the and assays. The obtained molecules showed potent and broad-spectrum activity in basic seizure models, namely, the maximal electroshock (MES) test, the 6 Hz (32 mA) seizure model, and notably, the 6 Hz (44 mA) model of pharmacoresistant seizures. Most potent compounds and displayed the following pharmacological values: ED = 64.3 mg/kg (MES), ED = 15.6 mg/kg (6 Hz, 32 mA), ED = 29.9 mg/kg (6 Hz, 44 mA), and ED = 34.9 mg/kg (MES), ED = 12.1 mg/kg (6 Hz, 32 mA), ED = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, and were effective in the PTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound was tested in the PTZ-induced kindling model, and then, its influence on glutamate and GABA levels in the hippocampus and cortex was evaluated by the high-performance liquid chromatography (HPLC) method. In addition, revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and ADME-Tox data proved favorable drug-like properties of . The patch-clamp recordings in rat cortical neurons showed that at a concentration of 10 μM significantly inhibited fast sodium currents. Therefore, seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.