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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Authors | Chris Bladen, Miyase Gözde Gündüz, Rahime Şimşek, Cihat Şafak, Gerald W Zamponi |
Journal | Pflugers Archiv : European journal of physiology
(Pflugers Arch)
Vol. 466
Issue 7
Pg. 1355-63
(Jul 2014)
ISSN: 1432-2013 [Electronic] Germany |
PMID | 24149495
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CACNA1H protein, human
- Calcium Channel Blockers
- Calcium Channels, L-Type
- Calcium Channels, T-Type
- Dihydropyridines
- 1,4-dihydropyridine
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Topics |
- Animals
- Calcium Channel Blockers
(chemical synthesis, pharmacology)
- Calcium Channels, L-Type
(metabolism)
- Calcium Channels, T-Type
(metabolism)
- Dihydropyridines
(chemistry, pharmacology)
- HEK293 Cells
- Humans
- Rats
- Structure-Activity Relationship
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