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

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

  • J Med Chem. 2026 May 14;69(9):10019-10045. doi: 10.1021/acs.jmedchem.5c02093.
Marcin Jakubiec 1,  Mirosław Zagaja 2,  Katarzyna Socała 3,  Michał Abram 1,  Szczepan Mogilski 4,  Gniewomir Latacz 5 6,  Małgorzata Szafarz 7,  Joanna Szala-Rycaj 2,  Joanna Karnafał-Ziembla 5,  Maja Kudrycka 6,  Nikola Gapińska 3 8,  Alan González Ibarra 9,  Justyna Turek 10,  Łukasz Gąsior 10,  Bernadeta Szewczyk 10,  Elżbieta Wyska 7,  Marta Andres-Mach 2,  Piotr Wlaź 3,  Krzysztof Kamiński 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
  • 2 Department of Experimental Pharmacology, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland.
  • 3 Biomedical Research Laboratory, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland.
  • 4 Department Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
  • 5 Department of Chemical Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
  • 6 Pharmacokinetics and Preliminary Toxicological Analysis Laboratory, Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, 30-688 Krakow, Poland.
  • 7 Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
  • 8 Doctoral School of Quantitative and Natural Sciences, Maria Curie-Skłodowska University, Weteranów 18, 20-038 Lublin, Poland.
  • 9 Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland.
  • 10 Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
PMID: 42065935 DOI: 10.1021/acs.jmedchem.5c02093
Abstract

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.

Figures
Products