2. Academic Validation
  3. Discovery and Profiling of New Multimodal Phenylglycinamide Derivatives as Potent Antiseizure and Antinociceptive Drug Candidates

Discovery and Profiling of New Multimodal Phenylglycinamide Derivatives as Potent Antiseizure and Antinociceptive Drug Candidates

  • ACS Chem Neurosci. 2024 Sep 4;15(17):3228-3256. doi: 10.1021/acschemneuro.4c00438.
Marcin Jakubiec 1,  Michał Abram 1,  Mirosław Zagaja 2,  Katarzyna Socała 3,  Vanja Panic 4,  Gniewomir Latacz 5,  Szczepan Mogilski 6,  Małgorzata Szafarz 7,  Joanna Szala-Rycaj 2,  Jerry Saunders 4,  Peter J West 4,  Dorota Nieoczym 3,  Katarzyna Przejczowska-Pomierny 7,  Bartłomiej Szulczyk 8,  Anna Krupa 9,  Elżbieta Wyska 7,  Piotr Wlaź 3,  Cameron S Metcalf 4,  Karen Wilcox 4,  Marta Andres-Mach 2,  Rafał M Kamiński 1,  Krzysztof Kamiński 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Cracow 30-688, Poland.
  • 2 Department of Experimental Pharmacology, Institute of Rural Health, Jaczewskiego 2, Lublin 20-950, Poland.
  • 3 Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, Lublin 20-033, Poland.
  • 4 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, United States.
  • 5 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Cracow 30-688, Poland.
  • 6 Department Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Cracow 30-688, Poland.
  • 7 Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Cracow 30-688, Poland.
  • 8 Chair and Department of Pharmacotherapy and Pharmaceutical Care, Centre for Preclinical Research and Technology, Medical University of Warsaw, Banacha 1B, Warsaw 02-097, Poland.
  • 9 Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Medyczna 9, Cracow 30-688, Poland.
PMID: 39166702 DOI: 10.1021/acschemneuro.4c00438
Abstract

We developed a focused series of original phenyl-glycinamide derivatives which showed potent activity across in vivo mouse seizure models, namely, maximal electroshock (MES) and 6 Hz (using both 32 and 44 mA current intensities) seizure models. Following intraperitoneal (i.p.) administration, compound (R)-32, which was identified as a lead molecule, demonstrated potent protection against all seizure models with ED50 values of 73.9 mg/kg (MES test), 18.8 mg/kg (6 Hz, 32 mA test), and 26.5 mg/kg (6 Hz, 44 mA test). Furthermore, (R)-32 demonstrated efficacy in both the PTZ-induced kindling paradigm and the ivPTZ seizure threshold test. The expression of Neurotrophic Factors, such as mature brain-derived neurotrophic factor (mBDNF) and nerve growth factor (NGF), in the hippocampus and/or cortex of mice, and the levels of glutamate and GABA were normalized after PTZ-induced kindling by (R)-32. Importantly, besides antiseizure activity, (R)-32 demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (i.p.). No influence on muscular strength and body temperature in mice was observed. Pharmacokinetic studies and in vitro ADME-Tox data (i.e., high metabolic stability in human liver microsomes, a weak influence on CYPs, no hepatotoxicity, satisfactory passive transport, etc.) proved favorable drug-like properties of (R)-32. Thermal stability of (R)-32 shown in thermogravimetry and differential scanning calorimetry gives the opportunity to develop innovative oral solid dosage forms loaded with this compound. The in vitro binding and functional assays indicated its multimodal mechanism of action. (R)-32, beyond TRPV1 antagonism, inhibited calcium and sodium currents at a concentration of 10 μM. Therefore, the data obtained in the current studies justify a more detailed preclinical development of (R)-32 for epilepsy and pain indications.

Keywords

antinociceptive activity; antiseizure activity; hybrid molecules; in vitro ADME-Tox studies; in vitro functional studies; multimechanistic compounds.

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