Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain
Neuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/4/407 |
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| author | Young-Hwan Jung Yeo Ok Kim Koon Mook Kang Hyung Gon Lee Borum Son Xuehao Han Eunseok Oh Siwon Kim Seon Hee Seo Jong-Hyun Park Ki Duk Park Woong Mo Kim Myung Ha Yoon Yong-Chul Kim |
| author_facet | Young-Hwan Jung Yeo Ok Kim Koon Mook Kang Hyung Gon Lee Borum Son Xuehao Han Eunseok Oh Siwon Kim Seon Hee Seo Jong-Hyun Park Ki Duk Park Woong Mo Kim Myung Ha Yoon Yong-Chul Kim |
| author_sort | Young-Hwan Jung |
| collection | DOAJ |
| description | Neuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an urgent need to develop new pharmaceutical agents to treat neuropathic pain. To date, highly specific agents that modulate a single target, such as receptors or ion channels, never progress to the clinic, which may reflect the diverse etiologies of neuropathic pain seen in the human patient population. Therefore, the development of multifunctional compounds exhibiting two or more pharmacological activities is an attractive strategy for addressing unmet medical needs for the treatment of neuropathic pain. To develop novel multifunctional compounds, key pharmacophores of currently used clinical pain drugs, including pregabalin, fluoxetine and serotonin analogs, were hybridized to the side chain of tianeptine, which has been used as an antidepressant. The biological activities of the hybrid analogs were evaluated at the human transporters of neurotransmitters, including serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT), as well as mu (μ) and kappa (κ) opioid receptors. The most advanced hybrid of these multifunctional compounds, <b>17</b>, exhibited multiple transporter inhibitory activities for the uptake of neurotransmitters with IC<sub>50</sub> values of 70 nM, 154 nM and 2.01 μM at hSERT, hNET and hDAT, respectively. Additionally, compound <b>17</b> showed partial agonism (EC<sub>50</sub> = 384 nM) at the μ-opioid receptor with no influence at the κ-opioid receptor. In in vivo pain animal experiments, the multifunctional compound <b>17</b> showed significantly reduced allodynia in a spinal nerve ligation (SNL) model by intrathecal administration, indicating that multitargeted strategies in single therapy could considerably benefit patients with multifactorial diseases, such as pain. |
| first_indexed | 2024-03-09T10:31:38Z |
| format | Article |
| id | doaj.art-f336e7f773a0407694da045b1a934c52 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T10:31:38Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-f336e7f773a0407694da045b1a934c522023-12-01T21:18:02ZengMDPI AGPharmaceuticals1424-82472022-03-0115440710.3390/ph15040407Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic PainYoung-Hwan Jung0Yeo Ok Kim1Koon Mook Kang2Hyung Gon Lee3Borum Son4Xuehao Han5Eunseok Oh6Siwon Kim7Seon Hee Seo8Jong-Hyun Park9Ki Duk Park10Woong Mo Kim11Myung Ha Yoon12Yong-Chul Kim13School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaDepartment of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju 61469, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaDepartment of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju 61469, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaDepartment of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju 61469, KoreaDepartment of Chemistry, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaConvergence Research Center for Brain Science, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaConvergence Research Center for Brain Science, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaConvergence Research Center for Brain Science, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaConvergence Research Center for Brain Science, Korea Institute of Science and Technology (KIST), Seoul 02792, KoreaDepartment of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju 61469, KoreaDepartment of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju 61469, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaNeuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an urgent need to develop new pharmaceutical agents to treat neuropathic pain. To date, highly specific agents that modulate a single target, such as receptors or ion channels, never progress to the clinic, which may reflect the diverse etiologies of neuropathic pain seen in the human patient population. Therefore, the development of multifunctional compounds exhibiting two or more pharmacological activities is an attractive strategy for addressing unmet medical needs for the treatment of neuropathic pain. To develop novel multifunctional compounds, key pharmacophores of currently used clinical pain drugs, including pregabalin, fluoxetine and serotonin analogs, were hybridized to the side chain of tianeptine, which has been used as an antidepressant. The biological activities of the hybrid analogs were evaluated at the human transporters of neurotransmitters, including serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT), as well as mu (μ) and kappa (κ) opioid receptors. The most advanced hybrid of these multifunctional compounds, <b>17</b>, exhibited multiple transporter inhibitory activities for the uptake of neurotransmitters with IC<sub>50</sub> values of 70 nM, 154 nM and 2.01 μM at hSERT, hNET and hDAT, respectively. Additionally, compound <b>17</b> showed partial agonism (EC<sub>50</sub> = 384 nM) at the μ-opioid receptor with no influence at the κ-opioid receptor. In in vivo pain animal experiments, the multifunctional compound <b>17</b> showed significantly reduced allodynia in a spinal nerve ligation (SNL) model by intrathecal administration, indicating that multitargeted strategies in single therapy could considerably benefit patients with multifactorial diseases, such as pain.https://www.mdpi.com/1424-8247/15/4/407neuropathic painmultifunctional compoundmultiple mechanisms of actiontianeptineopioid receptorneurotransmitter transporter |
| spellingShingle | Young-Hwan Jung Yeo Ok Kim Koon Mook Kang Hyung Gon Lee Borum Son Xuehao Han Eunseok Oh Siwon Kim Seon Hee Seo Jong-Hyun Park Ki Duk Park Woong Mo Kim Myung Ha Yoon Yong-Chul Kim Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain Pharmaceuticals neuropathic pain multifunctional compound multiple mechanisms of action tianeptine opioid receptor neurotransmitter transporter |
| title | Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain |
| title_full | Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain |
| title_fullStr | Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain |
| title_full_unstemmed | Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain |
| title_short | Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain |
| title_sort | development of dibenzothiazepine derivatives as multifunctional compounds for neuropathic pain |
| topic | neuropathic pain multifunctional compound multiple mechanisms of action tianeptine opioid receptor neurotransmitter transporter |
| url | https://www.mdpi.com/1424-8247/15/4/407 |
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