title: Design, synthesis, and pharmacological evaluation of haloperidol derivatives as novel potent calcium channel blockers with vasodilator activity.
abstract: Several haloperidol derivatives with a piperidine scaffold that was decorated at the nitrogen atom with different alkyl, benzyl, or substituted benzyl moieties were synthesized at our laboratory to establish a library of compounds with vasodilator activity. Compounds were screened for vasodilatory activity on isolated thoracic aorta rings from rats, and their quantitative structure-activity relationships (QSAR) were examined. Based on the result of QSAR, N-4-tert-butyl benzyl haloperidol chloride (16c) was synthesized and showed the most potent vasodilatory activity of all designed compounds. 16c dose-dependently inhibited the contraction caused by the influx of extracellular Ca(2+) in isolated thoracic aorta rings from rats. It concentration-dependently attenuated the calcium channel current and extracellular Ca(2+) influx, without affecting the intracellular Ca(2+) mobilization, in vascular smooth muscle cells from rats. 16c, possessing the N-4-tert-butyl benzyl piperidine structure, as a novel calcium antagonist, may be effective as a calcium channel blocker in cardiovascular disease.
authors: Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China.
authors: Yicun
authors: Y
authors: Chen
authors: Jinhong
authors: J
authors: Zheng
authors: Fuchun
authors: F
authors: Zheng
authors: Jinzhi
authors: J
authors: Wang
authors: Yanmei
authors: Y
authors: Zhang
authors: Fenfei
authors: F
authors: Gao
authors: Zhanqin
authors: Z
authors: Huang
authors: Ganggang
authors: G
authors: Shi
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011189:Potassium Chloride; D006220:Haloperidol; D002118:Calcium