title: Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Yi-Cun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Geneheal Biotechnology Co., Ltd, Guangzhou 510000, Guangdong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Shu-Ping
authors.initials: SP
authors.lastname: Zhong
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Fu-Chun
authors.initials: FC
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Fen-Fei
authors.initials: FF
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Yan-Shan
authors.initials: YS
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China.|Department of Cardiovascular Diseases, The First Affiliated Hospital, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Gang-Gang
authors.initials: GG
authors.lastname: Shi
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006220:Haloperidol / Q000031:analogs & derivatives*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D018613:Microscopy, Confocal; D062105:Molecular Docking Simulation; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D002121:Calcium Channel Blockers; D006220:Haloperidol
keywords: KCl-induced aortic ring contraction; calcium; novel calcium antagonists; synthesis