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

TitleStructure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors.
Publication TypeJournal Article
Year of Publication2012
AuthorsPajouhesh H, Feng Z-P, 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
JournalBioorg Med Chem Lett
Date Published2012 Jun 15
KeywordsAnalgesics, Animals, Calcium Channel Blockers, Calcium Channels, L-Type, Calcium Channels, N-Type, Disease Models, Animal, Ether-A-Go-Go Potassium Channels, Hyperalgesia, Neuralgia, Piperazines, Rats, Rats, Sprague-Dawley, Spinal Nerves, Structure-Activity Relationship

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.

Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID22579422
Grant List / / Canadian Institutes of Health Research / Canada
Faculty Member Reference: 
Frank Porreca, PhD
Todd Vanderah, PhD