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.
Original language | English |
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Pages (from-to) | 1355-1363 |
Number of pages | 9 |
Journal | Pflugers Archiv European Journal of Physiology |
Volume | 466 |
Issue number | 7 |
DOIs | |
Publication status | Published - 1 Jul 2014 |
Externally published | Yes |
Keywords
- Calcium channels
- 1,4-Dihydropyridine
- Cardiovascular
- Hypertension
- L-type
- T-type
- Aldosterone secretion
- Aldosterone secretion.