Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt
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Yi-Cun Chen1, Wei Zhu4, Shu-Ping Zhong2, Fu-Chun Zheng3, Fen-Fei Gao1, Yan-Mei Zhang1, Han Xu1, Yan-Shan Zheng1, Gang-Gang Shi1,5
1Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China
2Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
3Department of Pharmacy, the First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
4Geneheal Biotechnology Co., Ltd, Guangzhou 510000, Guangdong, China
5Department of Cardiovascular Diseases, the First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China
Gang-Gang Shi, e-mail: [email protected]
Keywords: calcium, novel calcium antagonists, KCl-induced aortic ring contraction, synthesis
Received: July 02, 2015 Accepted: October 06, 2015 Published: October 19, 2015
BACKGROUND AND PURPOSE: Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. The possible working mechanisms of these haloperidol derivatives were also explored.
EXPERIMENTAL APPROACH: Novel calcium antagonists were synthesized by amination. Compounds were screened for their activity of vasodilation on isolated thoracic aortic ring of rats. Their cardiac side effects were explored. The patch-clamp, confocal laser microscopy and the computer-fitting molecular docking experiments were employed to investigate the possible working mechanisms of these calcium antagonists.
RESULTS: The novel calcium antagonists, X1, X2 and X3 showed stronger vasodilation effect and less cardiac side effect than that of classical calcium antagonists. They blocked L-type calcium channels with an potent effect order of X1 > X2 > X3. Consistently, X1, X2 and X3 interacted with different regions of Ca2+-CaM-CaV1.2 with an affinity order of X1 > X2 > X3.
CONCLUSIONS: The new halopedidol derivatives X1, X2 and X3 are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application.
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