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.
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.
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Chemistry, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 136-701, Republic of Korea.
Ju-Hyeon
JH
Lee
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Seon Hee
SH
Seo
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Eun Jeong
EJ
Lim
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biotechnology, Yonsei University, 220, Seoul 120-749, Republic of Korea.
Nam-Chul
NC
Cho
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Ghilsoo
G
Nam
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Soon Bang
SB
Kang
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Ae Nim
AN
Pae
Department of Chemistry, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 136-701, Republic of Korea.
Nakcheol
N
Jeong
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea. Electronic address: gkeum@kist.re.kr.
Gyochang
G
Keum
D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009437:Neuralgia / Q000188:drug therapy*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
D000700:Analgesics; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; D011725:Pyridines; C032727:piperidine; C023666:pyridine
Allodynia; Neuropathic pain; Piperidine; T-type calcium channel blocker; Tetrahydropyridine