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

Research output: Contribution to journalArticle

9 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 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.

Original languageEnglish
Pages (from-to)246-257
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume74
DOIs
Publication statusPublished - 2014 Mar 3

Fingerprint

T-Type Calcium Channels
Calcium Channel Blockers
Neuralgia
Derivatives
Spinal Nerves
Pharmacokinetics
Hyperalgesia
Clamping devices
Ligation
Rats
Assays
Screening
Modulation
Ligands
Calcium
Pain
piperidine
azastene
Therapeutics

Keywords

  • Allodynia
  • Neuropathic pain
  • Piperidine
  • T-type calcium channel blocker
  • Tetrahydropyridine

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

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; Cho, Nam Chul; Nam, Ghilsoo; Kang, Soon Bang; Pae, Ae Nim; Jeong, Nakcheol; Keum, Gyochang.

In: European Journal of Medicinal Chemistry, Vol. 74, 03.03.2014, p. 246-257.

Research output: Contribution to journalArticle

@article{77213c6020ea423ebbfcebed6fd7b077,
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",
year = "2014",
month = "3",
day = "3",
doi = "10.1016/j.ejmech.2013.12.056",
language = "English",
volume = "74",
pages = "246--257",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - 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

AU - Lee, Ju Hyeon

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

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.

AB - 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.

KW - Allodynia

KW - Neuropathic pain

KW - Piperidine

KW - T-type calcium channel blocker

KW - Tetrahydropyridine

UR - http://www.scopus.com/inward/record.url?scp=84893194307&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893194307&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2013.12.056

DO - 10.1016/j.ejmech.2013.12.056

M3 - Article

VL - 74

SP - 246

EP - 257

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -