1,4‐Dihydropyridines: Effects of Chirality and Conformation on the Calcium Antagonist and Calcium Agonist Activities

TLDR

Since 1975, 1,4‑dihydropyridines have become indispensable calcium antagonists for cardiovascular disease, with about twenty derivatives still in clinical development, and intriguingly some enantiomers act as calcium agonists, making them valuable tools for studying calcium channels. This article aims to describe enantiomer separation methods, highlight structural differences between calcium antagonists and agonists, and explain their divergent pharmacological behaviors. The authors employ chiral separation techniques and structural comparisons to distinguish antagonist from agonist activity and elucidate the underlying mechanistic differences.

Abstract

Abstract 4‐Aryl‐l,4‐dihydropyridine‐3,5‐dicarboxylic diesters of the nifedipine type have become almost indispensable for the treatment of cardiovascular diseases since they first appeared on the market in 1975. There are some twenty derivatives currently under clinical development worldwide and work in this area is continuing undiminished. The 1,4‐dihydropyridines are the most effective of the calcium antagonists or calcium channel blockers. They are valued not only for their pharmacological effect, but also as a tool for the investigation of the calcium channel, particularly since the discovery that this class also includes compounds that have exactly the opposite action profile and are known as calcium agonists. There are even instances in which this reversal of activity is found between enantiomers. In view of the importance of chirality to pharmacological activity, the present article will describe methods for the separation of enantiomers, point out the structural differences between calcium antagonists and calcium agonists, and attempt to explain the difference in their behavior.