Design, synthesis, and pharmacological evaluation of haloperidol derivatives as novel potent calcium channel blockers with vasodilator activity.

Yicun Chen,Fenfei Gao,Ganggang Shi,Jinhong Zheng,Zhanqin Huang,Fuchun Zheng,Yanmei Zhang,Jinzhi Wang

doi:10.1371/journal.pone.0027673

Yicun Chen, Fenfei Gao + Show 6 more

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https://doi.org/10.1371/journal.pone.0027673

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Journal: PloS one	Publication Date: Nov 16, 2011
Citations: 32	License type: CC BY 4.0

Affiliation: Shantou University, Shantou University Medical College

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 Ca2+ in isolated thoracic aorta rings from rats. It concentration-dependently attenuated the calcium channel current and extracellular Ca2+ influx, without affecting the intracellular Ca2+ 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.

Highlights

Calcium is essential for life and is the most common signal transduction element in cells [1,2]
Calcium channel blockers play an important role in cardiovascular diseases, but better drugs are still needed for some clinical problem
We synthesized a series of haloperidol derivatives and we used the test of vasodilator effect on the rat isolated thoracic aorta rings with a high level of K+ (80 mM) to screen molecules for further studies, and examined the structure-activity relationship of compounds

Summary

Introduction

Calcium is essential for life and is the most common signal transduction element in cells [1,2]. The contraction of all types of muscle primarily depends on increased intracellular Ca2+ [3]. Calcium channel blockers constitute an important class of cardiovascular drugs. Members of this class are clinically useful in the treatment of cardiovascular disorders in which calcium plays a regulatory role. Most cannot be used to resolve clinical problems such as ischemia, reperfusion injury, and vascular structure remodeling [4]. Some of them have serious side effects. Better calcium channel blockers are still needed

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