Discovery, structure–activity relationship study, and oral analgesic efficacy of cyproheptadine derivatives possessing N-type calcium channel inhibitory activity

The synthesis, structure–activity relationship study, and biological testings of novel series of cyproheptadine derivatives with N-type calcium channel inhibitory activity were described. Antiallergic drug cyproheptadine (Cyp) is known to have inhibitory activities for L-type calcium channels in add...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2006-08, Vol.14 (15), p.5333-5339
Main Authors: Yamamoto, Takashi, Niwa, Seiji, Iwayama, Satoshi, Koganei, Hajime, Fujita, Shin-ichi, Takeda, Tomoko, Kito, Morikazu, Ono, Yukitsugu, Saitou, Yuki, Takahara, Akira, Iwata, Seinosuke, Yamamoto, Hiroshi, Shoji, Masataka
Format: Article
Language:English
Subjects:
Administration, Oral
Analgesic activity
Analgesics
Animals
Behavior, Animal - drug effects
Biological and medical sciences
Calcium Channel Blockers - chemical synthesis
Calcium Channel Blockers - chemistry
Calcium Channel Blockers - pharmacology
Calcium Channels, N-Type - drug effects
Cell Line, Tumor
Cyproheptadine
Cyproheptadine - analogs & derivatives
Cyproheptadine - chemistry
Cyproheptadine - pharmacology
Drug Design
Drug Evaluation, Preclinical
Formaldehyde - chemistry
Guinea Pigs
Humans
In Vitro Techniques
Male
Medical sciences
Molecular Structure
N-type calcium channel
Neuropharmacology
Pain - chemically induced
Pain Measurement - drug effects
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Receptors, Histamine - drug effects
Receptors, Serotonin - drug effects
Stereoisomerism
Structure-Activity Relationship
Structure–activity relationship study
Tumor Cells, Cultured
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Summary:The synthesis, structure–activity relationship study, and biological testings of novel series of cyproheptadine derivatives with N-type calcium channel inhibitory activity were described. Antiallergic drug cyproheptadine (Cyp) is known to have inhibitory activities for L-type calcium channels in addition to histamine and serotonin receptors. Since we found that Cyp had an inhibitory activity against N-type calcium channel, Cyp was optimized to obtain more selective N-type calcium channel blocker with analgesic action. As a consequence of the optimization, we found 13 with potent N-type calcium channel inhibitory activity which had lower inhibitory activities against L-type calcium channel, histamine (H 1), and serotonin (5-HT 2A) receptors than those of Cyp. 13 showed an oral analgesic activity in rat formalin-induced pain model.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2006.03.040