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Pflugers Arch. 2014 Jul;466(7):1355-63. doi: 10.1007/s00424-013-1376-z. Epub 2013 Oct 23.

Synthesis and evaluation of 1,4-dihydropyridine derivatives with calcium channel blocking activity.

Author information

1
Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Canada.

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.

PMID:
24149495
DOI:
10.1007/s00424-013-1376-z
[Indexed for MEDLINE]

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