Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

Hassan Pajouhesh, Zhong Ping Feng, Lingyun Zhang, Hossein Pajouhesh, Xinpo Jiang, Adam Hendricson, Haiheng Dong, Elizabeth Tringham, Yanbing Ding, Todd W. Vanderah, Frank Porreca, Francesco Belardetti, Gerald W. Zamponi, Lester A. Mitscher, Terrance P. Snutch

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (∼120-fold) and L-type (∼3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.

Original languageEnglish (US)
Pages (from-to)4153-4158
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number12
DOIs
StatePublished - Jun 15 2012

Keywords

  • L-Type calcium channel
  • N-Type calcium channel
  • Pain
  • Trimethoxybenzyl piperazine
  • hERG potassium channel

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Pajouhesh, H., Feng, Z. P., Zhang, L., Pajouhesh, H., Jiang, X., Hendricson, A., Dong, H., Tringham, E., Ding, Y., Vanderah, T. W., Porreca, F., Belardetti, F., Zamponi, G. W., Mitscher, L. A., & Snutch, T. P. (2012). Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors. Bioorganic and Medicinal Chemistry Letters, 22(12), 4153-4158. https://doi.org/10.1016/j.bmcl.2012.04.054