Referenced in: none

Automatically associated channels: Cav3.1 , Cav3.2 , Kv11.1

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.

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

Journal, date & volume: Eur J Med Chem, 2014 Mar 3 , 74, 246-57

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24480356

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(v)3.1 (α(1G)) and Ca(v)3.2 (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.