| 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 | Takuya Seko, Masashi Kato, Hiroshi Kohno, Shizuka Ono, Kazuya Hashimura, Yoshifumi Takenobu, Hideyuki Takimizu, Katsuhiko Nakai, Hitoshi Maegawa, Nobuo Katsube, Masaaki Toda
(Affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka, Japan. seko at ono.co.jp)
|
| Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 12
Issue 17
Pg. 2267-9
(Sep 2 2002)
ISSN: 0960-894X England |
| PMID | 12161113
(Publication Type: Journal Article)
|
| Chemical References |
- Analgesics
- Calcium Channel Blockers
- Calcium Channels, N-Type
- Cysteine
|
| Topics |
- Administration, Oral
- Analgesics
(administration & dosage, chemistry, pharmacology)
- Animals
- Calcium Channel Blockers
(administration & dosage, chemistry, pharmacology)
- Calcium Channels, N-Type
(drug effects)
- Constriction, Pathologic
- Cysteine
(analogs & derivatives)
- Drug Evaluation, Preclinical
- Hydrophobicity
- Inhibitory Concentration 50
- Pain
(chemically induced, drug therapy)
- Rats
- Structure-Activity Relationship
- Therapeutic Equivalency
|
