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

17 Citations (Scopus)

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

Fingerprint

N-Type Calcium Channels
Structure-Activity Relationship
Pain
L-Type Calcium Channels
Spinal Nerves
Potassium Channels
Calcium Channel Blockers
Neuralgia
Formaldehyde
Ligation
Animal Models
Rats
Animals
piperazine
1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine

Keywords

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

ASJC Scopus subject areas

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

Cite this

Pajouhesh, H., Feng, Z. P., Zhang, L., Pajouhesh, H., Jiang, X., Hendricson, 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

Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors. / Pajouhesh, Hassan; Feng, Zhong Ping; Zhang, Lingyun; Pajouhesh, Hossein; Jiang, Xinpo; Hendricson, Adam; Dong, Haiheng; Tringham, Elizabeth; Ding, Yanbing; Vanderah, Todd W; Porreca, Frank; Belardetti, Francesco; Zamponi, Gerald W.; Mitscher, Lester A.; Snutch, Terrance P.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 12, 15.06.2012, p. 4153-4158.

Research output: Contribution to journalArticle

Pajouhesh, H, Feng, ZP, Zhang, L, Pajouhesh, H, Jiang, X, Hendricson, A, Dong, H, Tringham, E, Ding, Y, Vanderah, TW, Porreca, F, Belardetti, F, Zamponi, GW, Mitscher, LA & Snutch, TP 2012, 'Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 12, pp. 4153-4158. https://doi.org/10.1016/j.bmcl.2012.04.054
Pajouhesh, Hassan ; Feng, Zhong Ping ; Zhang, Lingyun ; Pajouhesh, Hossein ; Jiang, Xinpo ; Hendricson, Adam ; Dong, Haiheng ; Tringham, Elizabeth ; Ding, Yanbing ; Vanderah, Todd W ; Porreca, Frank ; Belardetti, Francesco ; Zamponi, Gerald W. ; Mitscher, Lester A. ; Snutch, Terrance P. / Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 12. pp. 4153-4158.
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