Novel 3-Methoxypropanamide Derivatives as Potential Antiseizure and Antinociceptive Agents: Experimental Evidence from In Vitro and In Vivo Studies.

In this study, novel derivatives based on the 3-methoxypropanamide core were designed, synthesized, and evaluated in vitro and in vivo. These compounds demonstrated broad-spectrum antiseizure activity, with (R)-46 emerging as the lead candidate. Following intraperitoneal administration, (R)-46 showed ED50 values of 35.6 mg/kg (MES), 8.4 mg/kg (6 Hz, 32 mA), and 19.1 mg/kg (6 Hz, 44 mA), significantly elevating seizure thresholds in multiple models without affecting grip strength. Chronic treatment suppressed seizure progression in the PTZ kindling model, with minimal impact on hippocampal inflammatory markers or amino acids profile. Importantly, (R)-46 exhibited antinociceptive effects in formalin-, capsaicin-, oxaliplatin- and streptozotocin-induced pain models. Pharmacokinetic and in vitro ADME-Tox studies indicated favorable drug-like properties. Mechanistic studies suggest dual mode of action, including 5-HT2C receptor agonism and inhibition of voltage-gated sodium channels. These results support further preclinical development of (R)-46 as a promising candidate for treating epilepsy and pain-related disorders.