Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators

Cav1.2 and Cav1.3 are the main L- type Ca2+ channel subtypes in the brain. Cav1.3 channels have recently been implicated in the pathogenesis of Parkinson's disease. Therefore, Cav1.3- selective blockers are developed as promising neuroprotective drugs. We studied the pharmacological properties of a pyrimidine- 2,4,6- trione derivative (1-(3- chlorophenethyl)- 3cyclopentylpyrimidine- 2,4,6-(1H, 3H, 5H)- trione, Cp8) recently reported as the first highly selective Cav1.3 blocker. Here we show, in contrast to this previous study, that Cp8 reproducibly increases inward Ca2_ currents of Cav1.3 and Cav1.2 channels expressed in tsA- 201 cells by slowing activation, inactivation and enhancement of tail currents. Similar effects are also observed for native Cav1.3 and Cav1.2 channels in mouse chromaffin cells, while non- Ltype currents are unaffected. Evidence for a weak and non- selective inhibition of Cav1.3 and Cav1.2 currents is only observed in a minority of cells using Ba2_ as charge carrier. Therefore, our data identify pyrimidine- 2,4,6- triones as Ca2+ channel activators.