Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors
Background: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an...
| Main Authors: | , , , , , |
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| Format: | Article |
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Elsevier BV
2021
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| Online Access: | http://psasir.upm.edu.my/id/eprint/95272/ |
| _version_ | 1848862115812605952 |
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| author | Ayoub, Rami Jarrar, Qais Bashir Ali, Dalia Moshawih, Said Jarrar, Qais Bashir Hakim, Muhammad Nazrul Zakaria, Zainul Amiruddin |
| author_facet | Ayoub, Rami Jarrar, Qais Bashir Ali, Dalia Moshawih, Said Jarrar, Qais Bashir Hakim, Muhammad Nazrul Zakaria, Zainul Amiruddin |
| author_sort | Ayoub, Rami |
| building | UPM Institutional Repository |
| collection | Online Access |
| description | Background: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy. Method: α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations. Results: Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20 mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA. Conclusion: Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action. |
| first_indexed | 2025-11-15T13:11:54Z |
| format | Article |
| id | upm-95272 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-15T13:11:54Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-952722023-01-31T06:47:26Z http://psasir.upm.edu.my/id/eprint/95272/ Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors Ayoub, Rami Jarrar, Qais Bashir Ali, Dalia Moshawih, Said Jarrar, Qais Bashir Hakim, Muhammad Nazrul Zakaria, Zainul Amiruddin Background: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy. Method: α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations. Results: Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20 mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA. Conclusion: Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action. Elsevier BV 2021 Article PeerReviewed Ayoub, Rami and Jarrar, Qais Bashir and Ali, Dalia and Moshawih, Said and Jarrar, Qais Bashir and Hakim, Muhammad Nazrul and Zakaria, Zainul Amiruddin (2021) Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors. European Journal of Pharmaceutical Sciences, 163. art. no. 5865. pp. 1-9. ISSN 0928-0987 https://www.sciencedirect.com/science/article/pii/S0928098721001664?via%3Dihub 10.1016/j.ejps.2021.105865 |
| spellingShingle | Ayoub, Rami Jarrar, Qais Bashir Ali, Dalia Moshawih, Said Jarrar, Qais Bashir Hakim, Muhammad Nazrul Zakaria, Zainul Amiruddin Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors |
| title | Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors |
| title_full | Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors |
| title_fullStr | Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors |
| title_full_unstemmed | Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors |
| title_short | Synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on GABA, opioid and glutamate receptors |
| title_sort | synthesis of novel esters of mefenamic acid with pronounced anti-nociceptive effects and a proposed activity on gaba, opioid and glutamate receptors |
| url | http://psasir.upm.edu.my/id/eprint/95272/ http://psasir.upm.edu.my/id/eprint/95272/ http://psasir.upm.edu.my/id/eprint/95272/ |