Antagonism of L-type Ca²⁺ channels Ca_V1.3 and Ca _V1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics

The L-type calcium channel (LTCC) Ca_V1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through Ca_V1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a Ca _V1.3 antagonist selective over Ca_V1.2 is essential because Ca_V1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of Ca_V1.3 relative to Ca_V1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of Ca_V1.3 and Ca_V1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for Ca_V1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for Ca_V1.3 over Ca_V1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in Ca_V1.3 and Ca _V1.2 LTCCs are very similar.