Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model

Ju Hyeon Lee; Seon Hee Seo; Eun Jeong Lim; Nam Chul Cho; Ghilsoo Nam; Soon Bang Kang; Ae Nim Pae; Nakcheol Jeong; Gyochang Keum

doi:10.1016/j.ejmech.2013.12.056

Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model

Ju Hyeon Lee, Seon Hee Seo, Eun Jeong Lim, Nam Chul Cho, Ghilsoo Nam, Soon Bang Kang, Ae Nim Pae, Nakcheol Jeong, Gyochang Keum

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Ca_v3.1 (α _1G) and Ca_v3.2 (α_1H) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α_1G and α_1H subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.

Original language	English
Pages (from-to)	246-257
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	74
DOIs	https://doi.org/10.1016/j.ejmech.2013.12.056
Publication status	Published - 2014 Mar 3

Keywords

Allodynia
Neuropathic pain
Piperidine
T-type calcium channel blocker
Tetrahydropyridine

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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Lee, J. H., Seo, S. H., Lim, E. J., Cho, N. C., Nam, G., Kang, S. B., Pae, A. N., Jeong, N., & Keum, G. (2014). Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model. European Journal of Medicinal Chemistry, 74, 246-257. https://doi.org/10.1016/j.ejmech.2013.12.056

Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model. / Lee, Ju Hyeon; Seo, Seon Hee; Lim, Eun Jeong et al.
In: European Journal of Medicinal Chemistry, Vol. 74, 03.03.2014, p. 246-257.

Research output: Contribution to journal › Article › peer-review

Lee, JH, Seo, SH, Lim, EJ, Cho, NC, Nam, G, Kang, SB, Pae, AN, Jeong, N & Keum, G 2014, 'Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model', European Journal of Medicinal Chemistry, vol. 74, pp. 246-257. https://doi.org/10.1016/j.ejmech.2013.12.056

Lee JH, Seo SH, Lim EJ, Cho NC, Nam G, Kang SB et al. Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model. European Journal of Medicinal Chemistry. 2014 Mar 3;74:246-257. doi: 10.1016/j.ejmech.2013.12.056

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title = "Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model",

abstract = "New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Cav3.1 (α 1G) and Cav3.2 (α1H) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α1G and α1H subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.",

keywords = "Allodynia, Neuropathic pain, Piperidine, T-type calcium channel blocker, Tetrahydropyridine",

author = "Lee, {Ju Hyeon} and Seo, {Seon Hee} and Lim, {Eun Jeong} and Cho, {Nam Chul} and Ghilsoo Nam and Kang, {Soon Bang} and Pae, {Ae Nim} and Nakcheol Jeong and Gyochang Keum",

note = "Funding Information: This research was supported by the KIST Institutional Program ( 2E23870 ). We thank Prof. Perez-Reyes (Department of Pharmacology, University of Virginia) for providing HEK293/Ca v 3.1 and Ca v 3.2 cells. ",

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AU - Seo, Seon Hee

AU - Lim, Eun Jeong

AU - Cho, Nam Chul

AU - Nam, Ghilsoo

AU - Kang, Soon Bang

AU - Pae, Ae Nim

AU - Jeong, Nakcheol

AU - Keum, Gyochang

N1 - Funding Information: This research was supported by the KIST Institutional Program ( 2E23870 ). We thank Prof. Perez-Reyes (Department of Pharmacology, University of Virginia) for providing HEK293/Ca v 3.1 and Ca v 3.2 cells.

PY - 2014/3/3

Y1 - 2014/3/3

N2 - New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Cav3.1 (α 1G) and Cav3.2 (α1H) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α1G and α1H subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.

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Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4- phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model

Abstract

Keywords

ASJC Scopus subject areas

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