title: L-Cysteine based N-type calcium channel blockers: structure-activity relationships of the C-terminal lipophilic moiety, and oral analgesic efficacy in rat pain models.
abstract: This study was performed to determine the structure-activity relationships (SAR) of L-cysteine based N-type calcium channel blockers. Basic nitrogen was introduced into the C-terminal lipophilic moiety of L-cysteine with a view toward improvement of its physicochemical properties. L-Cysteine derivative 9 was found to be a potent and selective N-type calcium channel blocker with IC(50) of 0.33 microM in calcium influx assay using IMR-32 cells and was 15-fold selective for N-type calcium channels over L-type channels. Compound 9 showed improved oral analgesic efficacy in the rat formalin induced pain model and the rat chronic constriction injury (CCI) model, which is one of the most reliable models of chronic neuropathic pain, without any significant effect on blood pressure or neurological behavior.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka, Japan. seko@ono.co.jp
authors.forename: Takuya
authors.initials: T
authors.lastname: Seko
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kohno
authors.forename: Shizuka
authors.initials: S
authors.lastname: Ono
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hashimura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takenobu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takimizu
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Katsube
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D003251:Constriction, Pathologic; D003545:Cysteine / Q000031:analogs & derivatives*; D004353:Drug Evaluation, Preclinical; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D013329:Structure-Activity Relationship; D013810:Therapeutic Equivalency
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D003545:Cysteine