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Synthesis and Evaluation of 1,4-Dihydropyridine Derivatives with Calcium Channel Blocking Activity

  • Ion channels, receptors and transporters
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Abstract

1,4-Dihydropyridines (DHPs) are an important class of L-type calcium channel blockers that are used to treat conditions such as hypertension and angina. Their primary target in the cardiovascular system is the Cav1.2 L-type calcium channel isoform, however, a number of DHPs also block low-voltage-activated T-type calcium channels. Here, we describe the synthesis of a series of novel DHP derivatives that have a condensed 1,4-DHP ring system (hexahydroquinoline) and report on their abilities to block both L- and T-type calcium channels. Within this series of compounds, modification of a key ester moiety not only regulates the blocking affinity for both L- and T-type channels, but also allows for the development of DHPs with 30-fold selectivity for T-type channels over the L-type. Our data suggest that a condensed dihydropyridine-based scaffold may serve as a pharmacophore for a new class of T-type selective inhibitors.

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Acknowledgments

This work was supported by operating grants to GWZ from the Canadian Institutes of Health Research. GWZ is a Canada Research Chair and an Alberta Innovates—Health Solutions (AI-HS) Scientist. CB holds a T. Chen Fong studentship and an AI-HS studentship award.

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Correspondence to Gerald W. Zamponi.

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Bladen, C., Gündüz, M.G., Şimşek, R. et al. Synthesis and Evaluation of 1,4-Dihydropyridine Derivatives with Calcium Channel Blocking Activity. Pflugers Arch - Eur J Physiol 466, 1355–1363 (2014). https://doi.org/10.1007/s00424-013-1376-z

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