New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants
In the present study, a focused combinatorial chemistry approach was applied to merge structural fragments of well-known TRPV1 antagonists with a potent anticonvulsant lead compound, <b>KA-104</b>, that was previously discovered by our group. Consequently, a series of 22 original compoun...
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MDPI AG
2022-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/12/1862 |
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| author | Marcin Jakubiec Michał Abram Mirosław Zagaja Marta Andres-Mach Aleksandra Szewczyk Gniewomir Latacz Bartłomiej Szulczyk Katarzyna Socała Dorota Nieoczym Piotr Wlaź Cameron S. Metcalf Karen Wilcox Rafał M. Kamiński Krzysztof Kamiński |
| author_facet | Marcin Jakubiec Michał Abram Mirosław Zagaja Marta Andres-Mach Aleksandra Szewczyk Gniewomir Latacz Bartłomiej Szulczyk Katarzyna Socała Dorota Nieoczym Piotr Wlaź Cameron S. Metcalf Karen Wilcox Rafał M. Kamiński Krzysztof Kamiński |
| author_sort | Marcin Jakubiec |
| collection | DOAJ |
| description | In the present study, a focused combinatorial chemistry approach was applied to merge structural fragments of well-known TRPV1 antagonists with a potent anticonvulsant lead compound, <b>KA-104</b>, that was previously discovered by our group. Consequently, a series of 22 original compounds has been designed, synthesized, and characterized in the in vivo and in vitro assays. The obtained compounds showed robust in vivo antiseizure activity in the maximal electroshock (MES) test and in the 6 Hz seizure model (using both 32 and 44 mA current intensities). The most potent compounds <b>53</b> and <b>60</b> displayed the following pharmacological profile: ED<sub>50</sub> = 89.7 mg/kg (MES), ED<sub>50</sub> = 29.9 mg/kg (6 Hz, 32 mA), ED<sub>50</sub> = 68.0 mg/kg (6 Hz, 44 mA), and ED<sub>50</sub> = 73.6 mg/kg (MES), ED<sub>50</sub> = 24.6 mg/kg (6 Hz, 32 mA), and ED<sub>50</sub> = 56.3 mg/kg (6 Hz, 44 mA), respectively. Additionally, <b>53</b> and <b>60</b> were effective in the <i>iv</i>PTZ seizure threshold and had no influence on the grip strength and body temperature in mice. The in vitro binding and functional assays indicated a multimodal mechanism of action for <b>53</b> and <b>60</b>. These molecules, beyond TRPV1 antagonism, inhibited calcium currents and fast sodium currents in patch-clamp assays. Further studies proved beneficial in vitro ADME-Tox properties for <b>53</b> and <b>60</b> (i.e., high metabolic stability, weak influence on CYPs, no neurotoxicity, etc.). Overall, <b>53</b> and <b>60</b> seem to be interesting candidates for future preclinical development in epilepsy and pain indications due to their interaction with the TRPV1 channel. |
| first_indexed | 2024-03-10T00:10:18Z |
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| id | doaj.art-9d34a801f4aa4feab4747cefcea04a31 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T00:10:18Z |
| publishDate | 2022-06-01 |
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| series | Cells |
| spelling | doaj.art-9d34a801f4aa4feab4747cefcea04a312023-11-23T16:00:31ZengMDPI AGCells2073-44092022-06-011112186210.3390/cells11121862New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum AnticonvulsantsMarcin Jakubiec0Michał Abram1Mirosław Zagaja2Marta Andres-Mach3Aleksandra Szewczyk4Gniewomir Latacz5Bartłomiej Szulczyk6Katarzyna Socała7Dorota Nieoczym8Piotr Wlaź9Cameron S. Metcalf10Karen Wilcox11Rafał M. Kamiński12Krzysztof Kamiński13Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandIsobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, PolandIsobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, PolandIsobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, PolandDepartment of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, PolandDepartment of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, PolandDepartment of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, PolandDepartment of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USADepartment of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USADepartment of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandIn the present study, a focused combinatorial chemistry approach was applied to merge structural fragments of well-known TRPV1 antagonists with a potent anticonvulsant lead compound, <b>KA-104</b>, that was previously discovered by our group. Consequently, a series of 22 original compounds has been designed, synthesized, and characterized in the in vivo and in vitro assays. The obtained compounds showed robust in vivo antiseizure activity in the maximal electroshock (MES) test and in the 6 Hz seizure model (using both 32 and 44 mA current intensities). The most potent compounds <b>53</b> and <b>60</b> displayed the following pharmacological profile: ED<sub>50</sub> = 89.7 mg/kg (MES), ED<sub>50</sub> = 29.9 mg/kg (6 Hz, 32 mA), ED<sub>50</sub> = 68.0 mg/kg (6 Hz, 44 mA), and ED<sub>50</sub> = 73.6 mg/kg (MES), ED<sub>50</sub> = 24.6 mg/kg (6 Hz, 32 mA), and ED<sub>50</sub> = 56.3 mg/kg (6 Hz, 44 mA), respectively. Additionally, <b>53</b> and <b>60</b> were effective in the <i>iv</i>PTZ seizure threshold and had no influence on the grip strength and body temperature in mice. The in vitro binding and functional assays indicated a multimodal mechanism of action for <b>53</b> and <b>60</b>. These molecules, beyond TRPV1 antagonism, inhibited calcium currents and fast sodium currents in patch-clamp assays. Further studies proved beneficial in vitro ADME-Tox properties for <b>53</b> and <b>60</b> (i.e., high metabolic stability, weak influence on CYPs, no neurotoxicity, etc.). Overall, <b>53</b> and <b>60</b> seem to be interesting candidates for future preclinical development in epilepsy and pain indications due to their interaction with the TRPV1 channel.https://www.mdpi.com/2073-4409/11/12/1862hybrid moleculesmultimodal/multi-target compoundsamino acid derivativesantiseizure activityin vitro binding/functional studiesADME-Tox properties |
| spellingShingle | Marcin Jakubiec Michał Abram Mirosław Zagaja Marta Andres-Mach Aleksandra Szewczyk Gniewomir Latacz Bartłomiej Szulczyk Katarzyna Socała Dorota Nieoczym Piotr Wlaź Cameron S. Metcalf Karen Wilcox Rafał M. Kamiński Krzysztof Kamiński New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants Cells hybrid molecules multimodal/multi-target compounds amino acid derivatives antiseizure activity in vitro binding/functional studies ADME-Tox properties |
| title | New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants |
| title_full | New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants |
| title_fullStr | New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants |
| title_full_unstemmed | New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants |
| title_short | New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants |
| title_sort | new phenylglycinamide derivatives with hybrid structure as candidates for new broad spectrum anticonvulsants |
| topic | hybrid molecules multimodal/multi-target compounds amino acid derivatives antiseizure activity in vitro binding/functional studies ADME-Tox properties |
| url | https://www.mdpi.com/2073-4409/11/12/1862 |
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