Marcin Jakubiec, Michał Abram, Mirosław Zagaja, Katarzyna Socała, Vanja Panic, Gniewomir Latacz, Szczepan Mogilski, Małgorzata Szafarz, Joanna Szala-Rycaj, Jerry Saunders, Peter J. West, Dorota Nieoczym, Katarzyna Przejczowska-Pomierny, Bartłomiej Szulczyk, Anna Krupa, Elżbieta Wyska, Piotr Wlaź, Cameron S. Metcalf, Karen Wilcox, Marta Andres-Mach, Rafał M. Kamiński and Krzysztof Kamiński*,
{"title":"作为强效抗癫痫和抗癫痫药物候选物的新型多模式苯基甘氨酰胺衍生物的发现和剖析","authors":"Marcin Jakubiec, Michał Abram, Mirosław Zagaja, Katarzyna Socała, Vanja Panic, Gniewomir Latacz, Szczepan Mogilski, Małgorzata Szafarz, Joanna Szala-Rycaj, Jerry Saunders, Peter J. West, Dorota Nieoczym, Katarzyna Przejczowska-Pomierny, Bartłomiej Szulczyk, Anna Krupa, Elżbieta Wyska, Piotr Wlaź, Cameron S. Metcalf, Karen Wilcox, Marta Andres-Mach, Rafał M. Kamiński and Krzysztof Kamiński*, ","doi":"10.1021/acschemneuro.4c0043810.1021/acschemneuro.4c00438","DOIUrl":null,"url":null,"abstract":"<p >We developed a focused series of original phenyl-glycinamide derivatives which showed potent activity across <i>in vivo</i> mouse seizure models, namely, maximal electroshock (MES) and 6 Hz (using both 32 and 44 mA current intensities) seizure models. Following intraperitoneal (<i>i.p</i>.) administration, compound <b>(</b><b><i>R</i></b><b>)-32</b>, which was identified as a lead molecule, demonstrated potent protection against all seizure models with ED<sub>50</sub> 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, <b>(</b><b><i>R</i></b><b>)-32</b> demonstrated efficacy in both the PTZ-induced kindling paradigm and the <i>iv</i>PTZ 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 <b>(<i>R</i>)-32</b>. Importantly, besides antiseizure activity, (<b><i>R</i></b>)<b>-32</b> demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (<i>i.p</i>.). No influence on muscular strength and body temperature in mice was observed. Pharmacokinetic studies and <i>in vitro</i> ADME-Tox data (<i>i.e.</i>, high metabolic stability in human liver microsomes, a weak influence on CYPs, no hepatotoxicity, satisfactory passive transport, <i>etc.</i>) proved favorable drug-like properties of (<b><i>R</i></b>)<b>-32</b>. Thermal stability of (<b><i>R</i></b>)-<b>32</b> shown in thermogravimetry and differential scanning calorimetry gives the opportunity to develop innovative oral solid dosage forms loaded with this compound. The <i>in vitro</i> binding and functional assays indicated its multimodal mechanism of action. (<b><i>R</i></b>)<b>-32</b>, 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 (<b><i>R</i></b>)<b>-32</b> for epilepsy and pain indications.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00438","citationCount":"0","resultStr":"{\"title\":\"Discovery and Profiling of New Multimodal Phenylglycinamide Derivatives as Potent Antiseizure and Antinociceptive Drug Candidates\",\"authors\":\"Marcin Jakubiec, Michał Abram, Mirosław Zagaja, Katarzyna Socała, Vanja Panic, Gniewomir Latacz, Szczepan Mogilski, Małgorzata Szafarz, Joanna Szala-Rycaj, Jerry Saunders, Peter J. 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Furthermore, <b>(</b><b><i>R</i></b><b>)-32</b> demonstrated efficacy in both the PTZ-induced kindling paradigm and the <i>iv</i>PTZ 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 <b>(<i>R</i>)-32</b>. Importantly, besides antiseizure activity, (<b><i>R</i></b>)<b>-32</b> demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (<i>i.p</i>.). No influence on muscular strength and body temperature in mice was observed. 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Discovery and Profiling of New Multimodal Phenylglycinamide Derivatives as Potent Antiseizure and Antinociceptive Drug Candidates
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.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research