Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt

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 (X(1)), N-m-methoxybenzyl (X(2)) and N-o-methoxybenzyl (X(3)) 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, X(1), X(2) and X(3) 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 X(1) > X(2) > X(3). Consistently, X(1), X(2) and X(3) interacted with different regions of Ca(2+)-CaM-CaV1.2 with an affinity order of X(1) > X(2) > X(3). CONCLUSIONS: The new halopedidol derivatives X(1), X(2) and X(3) are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application.