Novel Alaninamide Derivatives with Drug-like Potential for Development as Antiseizure and Antinociceptive Therapies─In Vitro and In Vivo Characterization
Marcin Jakubiec, Michał Abram, Mirosław Zagaja, Marta Andres-Mach, Joanna Szala-Rycaj, Gniewomir Latacz, Ewelina Honkisz-Orzechowska, Szczepan Mogilski, Monika Kubacka, Małgorzata Szafarz, Krzysztof Pociecha, Katarzyna Przejczowska-Pomierny, Elżbieta Wyska, Katarzyna Socała, Dorota Nieoczym, Bartłomiej Szulczyk, Piotr Wlaź, Cameron S. Metcalf, Karen Wilcox, Rafał M. Kamiński and Krzysztof Kamiński*,
{"title":"Novel Alaninamide Derivatives with Drug-like Potential for Development as Antiseizure and Antinociceptive Therapies─In Vitro and In Vivo Characterization","authors":"Marcin Jakubiec, Michał Abram, Mirosław Zagaja, Marta Andres-Mach, Joanna Szala-Rycaj, Gniewomir Latacz, Ewelina Honkisz-Orzechowska, Szczepan Mogilski, Monika Kubacka, Małgorzata Szafarz, Krzysztof Pociecha, Katarzyna Przejczowska-Pomierny, Elżbieta Wyska, Katarzyna Socała, Dorota Nieoczym, Bartłomiej Szulczyk, Piotr Wlaź, Cameron S. Metcalf, Karen Wilcox, Rafał M. Kamiński and Krzysztof Kamiński*, ","doi":"10.1021/acschemneuro.4c00013","DOIUrl":null,"url":null,"abstract":"<p >In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the <i>in vivo</i> and <i>in vitro</i> 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 <b>26</b> and <b>28</b> displayed the following pharmacological values: ED<sub>50</sub> = 64.3 mg/kg (MES), ED<sub>50</sub> = 15.6 mg/kg (6 Hz, 32 mA), ED<sub>50</sub> = 29.9 mg/kg (6 Hz, 44 mA), and ED<sub>50</sub> = 34.9 mg/kg (MES), ED<sub>50</sub> = 12.1 mg/kg (6 Hz, 32 mA), ED<sub>50</sub> = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, <b>26</b> and <b>28</b> were effective in the <i>iv</i>PTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound <b>28</b> 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, <b>28</b> revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and <i>in vitro</i> ADME-Tox data proved favorable drug-like properties of <b>28</b>. The patch-clamp recordings in rat cortical neurons showed that <b>28</b> at a concentration of 10 μM significantly inhibited fast sodium currents. Therefore, <b>28</b> seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00013","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acschemneuro.4c00013","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the in vivo and in vitro 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 26 and 28 displayed the following pharmacological values: ED50 = 64.3 mg/kg (MES), ED50 = 15.6 mg/kg (6 Hz, 32 mA), ED50 = 29.9 mg/kg (6 Hz, 44 mA), and ED50 = 34.9 mg/kg (MES), ED50 = 12.1 mg/kg (6 Hz, 32 mA), ED50 = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, 26 and 28 were effective in the ivPTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound 28 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, 28 revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and in vitro ADME-Tox data proved favorable drug-like properties of 28. The patch-clamp recordings in rat cortical neurons showed that 28 at a concentration of 10 μM significantly inhibited fast sodium currents. Therefore, 28 seems to be an interesting candidate for future preclinical development in 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