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

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.

• 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)

Chemical References

• CACNA1H protein, human
• Calcium Channel Blockers
• Calcium Channels, L-Type
• Calcium Channels, T-Type
• Dihydropyridines
• 1,4-dihydropyridine

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