Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides
We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (M...
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MDPI AG
2021-12-01
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/13092 |
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| author | Michał Abram Marcin Jakubiec Anna Rapacz Szczepan Mogilski Gniewomir Latacz Bartłomiej Szulczyk Małgorzata Szafarz Katarzyna Socała Dorota Nieoczym Elżbieta Wyska Piotr Wlaź Rafał M. Kamiński Krzysztof Kamiński |
| author_facet | Michał Abram Marcin Jakubiec Anna Rapacz Szczepan Mogilski Gniewomir Latacz Bartłomiej Szulczyk Małgorzata Szafarz Katarzyna Socała Dorota Nieoczym Elżbieta Wyska Piotr Wlaź Rafał M. Kamiński Krzysztof Kamiński |
| author_sort | Michał Abram |
| collection | DOAJ |
| description | We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (<i>sc</i>PTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound <b>14</b> showed the most robust anticonvulsant activity (ED<sub>50</sub> MES = 49.6 mg/kg, ED<sub>50</sub> 6 Hz (32 mA) = 31.3 mg/kg, ED<sub>50</sub><i>sc</i>PTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED<sub>50</sub> = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound <b>14</b> revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound <b>14</b> showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound <b>14</b> is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound <b>14</b> on the viability of neuroblastoma SH-SY5Y cells. |
| first_indexed | 2024-03-10T04:52:31Z |
| format | Article |
| id | doaj.art-a1a273109e184c6a9330b827ad6cea4d |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:52:31Z |
| publishDate | 2021-12-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a1a273109e184c6a9330b827ad6cea4d2023-11-23T02:33:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122231309210.3390/ijms222313092Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-AcetamidesMichał Abram0Marcin Jakubiec1Anna Rapacz2Szczepan Mogilski3Gniewomir Latacz4Bartłomiej Szulczyk5Małgorzata Szafarz6Katarzyna Socała7Dorota Nieoczym8Elżbieta Wyska9Piotr Wlaź10Rafał M. Kamiński11Krzysztof Kamiński12Department 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, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, 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 Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, PolandDepartment of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, PolandDepartment of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, PolandDepartment of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, PolandDepartment 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, PolandWe report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (<i>sc</i>PTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound <b>14</b> showed the most robust anticonvulsant activity (ED<sub>50</sub> MES = 49.6 mg/kg, ED<sub>50</sub> 6 Hz (32 mA) = 31.3 mg/kg, ED<sub>50</sub><i>sc</i>PTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED<sub>50</sub> = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound <b>14</b> revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound <b>14</b> showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound <b>14</b> is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound <b>14</b> on the viability of neuroblastoma SH-SY5Y cells.https://www.mdpi.com/1422-0067/22/23/13092pyrrolidine-2,5-dionesaltshybrid compoundsanticonvulsant activityantinociceptive activityelectrophysiology |
| spellingShingle | Michał Abram Marcin Jakubiec Anna Rapacz Szczepan Mogilski Gniewomir Latacz Bartłomiej Szulczyk Małgorzata Szafarz Katarzyna Socała Dorota Nieoczym Elżbieta Wyska Piotr Wlaź Rafał M. Kamiński Krzysztof Kamiński Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides International Journal of Molecular Sciences pyrrolidine-2,5-dione salts hybrid compounds anticonvulsant activity antinociceptive activity electrophysiology |
| title | Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides |
| title_full | Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides |
| title_fullStr | Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides |
| title_full_unstemmed | Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides |
| title_short | Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides |
| title_sort | identification of new compounds with anticonvulsant and antinociceptive properties in a group of 3 substituted 2 5 dioxo pyrrolidin 1 yl phenyl acetamides |
| topic | pyrrolidine-2,5-dione salts hybrid compounds anticonvulsant activity antinociceptive activity electrophysiology |
| url | https://www.mdpi.com/1422-0067/22/23/13092 |
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