Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain

Jung, Young-Hwan; Kim, Yeo Ok; Kang, Koon Mook; Lee, Hyung Gon; Son, Borum; Han, Xuehao; Oh, Eunseok; Kim, Siwon; Seo, Seon Hee; Park, Jong-Hyun; Park, Ki Duk; Kim, Woong Mo; Yoon, Myung Ha; Kim, Yong-Chul

doi:10.3390/ph15040407

Open AccessArticle

Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain

by

Young-Hwan Jung

^1,†,

Yeo Ok Kim

^2,†,

Koon Mook Kang

^1,†,

Hyung Gon Lee

^2,3,

Borum Son

¹,

Xuehao Han

^2,3,

Eunseok Oh

⁴,

Siwon Kim

⁵,

Seon Hee Seo

⁵,

Jong-Hyun Park

^5,6,

Ki Duk Park

^5,6

,

Woong Mo Kim

^2,3,

Myung Ha Yoon

^2,* and

Yong-Chul Kim

^1,7,*

¹

School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea

²

Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju 61469, Korea

³

Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, Korea

⁴

Department of Chemistry, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea

⁵

Convergence Research Center for Brain Science, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea

⁶

Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea

⁷

Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Pharmaceuticals 2022, 15(4), 407; https://doi.org/10.3390/ph15040407

Submission received: 22 February 2022 / Revised: 18 March 2022 / Accepted: 23 March 2022 / Published: 27 March 2022

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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Abstract

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, 17, exhibited multiple transporter inhibitory activities for the uptake of neurotransmitters with IC₅₀ values of 70 nM, 154 nM and 2.01 μM at hSERT, hNET and hDAT, respectively. Additionally, compound 17 showed partial agonism (EC₅₀ = 384 nM) at the μ-opioid receptor with no influence at the κ-opioid receptor. In in vivo pain animal experiments, the multifunctional compound 17 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.

Keywords: neuropathic pain; multifunctional compound; multiple mechanisms of action; tianeptine; opioid receptor; neurotransmitter transporter

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MDPI and ACS Style

Jung, Y.-H.; Kim, Y.O.; Kang, K.M.; Lee, H.G.; Son, B.; Han, X.; Oh, E.; Kim, S.; Seo, S.H.; Park, J.-H.; et al. Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain. Pharmaceuticals 2022, 15, 407. https://doi.org/10.3390/ph15040407

AMA Style

Jung Y-H, Kim YO, Kang KM, Lee HG, Son B, Han X, Oh E, Kim S, Seo SH, Park J-H, et al. Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain. Pharmaceuticals. 2022; 15(4):407. https://doi.org/10.3390/ph15040407

Chicago/Turabian Style

Jung, Young-Hwan, Yeo Ok Kim, Koon Mook Kang, Hyung Gon Lee, Borum Son, Xuehao Han, Eunseok Oh, Siwon Kim, Seon Hee Seo, Jong-Hyun Park, and et al. 2022. "Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain" Pharmaceuticals 15, no. 4: 407. https://doi.org/10.3390/ph15040407

APA Style

Jung, Y.-H., Kim, Y. O., Kang, K. M., Lee, H. G., Son, B., Han, X., Oh, E., Kim, S., Seo, S. H., Park, J.-H., Park, K. D., Kim, W. M., Yoon, M. H., & Kim, Y.-C. (2022). Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain. Pharmaceuticals, 15(4), 407. https://doi.org/10.3390/ph15040407

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Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain

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