title: Scaffold-based design and synthesis of potent N-type calcium channel blockers.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhang
authors.forename: Hossein
authors.initials: H
authors.lastname: Pajouhesh
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Ding
authors.forename: Francesco
authors.initials: F
authors.lastname: Belardetti
authors.forename: Hassan
authors.initials: H
authors.lastname: Pajouhesh
authors.forename: David
authors.initials: D
authors.lastname: Dolphin
authors.forename: Lester A
authors.initials: LA
authors.lastname: Mitscher
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000627:therapeutic use*; D000818:Animals; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020864:Calcium Channels, N-Type / Q000187:drug effects; D020747:Calcium Channels, T-Type / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type