Research & Teaching Faculty

Scaffold-based design and synthesis of potent N-type calcium channel blockers

TitleScaffold-based design and synthesis of potent N-type calcium channel blockers
Publication TypeJournal Article
Year of Publication2009
AuthorsZamponi, GW, Feng, ZP, Zhang, LY, Pajouhesh, H, Ding, YB, Belardetti, F, Dolphin, D, Mitscher, LA, Snutch, TP
JournalBioorganic & Medicinal Chemistry Letters
Date PublishedNov
Type of ArticleArticle
ISBN Number0960-894X
KeywordsBRAIN, CA2+ CHANNELS, Calcium channel blocker, Diphenylmethylpiperazine, N-type, OMEGA-CONOTOXIN, PAIN, SUBUNIT

The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium channel. (C) 2009 Elsevier Ltd. All rights reserved.

URL<Go to ISI>://000271029600045