The dihydropyridine analogue cerebrocrast blocks both T-type and L-type calcium currents.
Cerebrocrast is a novel lipophilic dihydropyridine derivative with potential neuroprotective and antidiabetic properties. We have analyzed its interaction with L-type (CaV1.2b) and T-type (CaV3.1) calcium channels using a whole-cell patch clamp in HEK 293 cells. Cerebrocrast inhibited current flux through both CaV1.2b and CaV3.1 channels. In both cases, the drug was about 10-fold less effective than neutral dihydropyridines, but more efficient than the charged dihydropyridine amlodipine. IC50 values for the CaV1.2b channel were 586 +/- 96 nmol/L and 178 +/- 78 nmol/L at holding potentials of -80 mV and -50 mV, respectively. Approximately 50 micromol/L of cerebrocrast was needed to block 50% of the current amplitude in the CaV3.1 channel, but this inhibition was not facilitated by shifting the holding potential from -100 mV to -70 mV. Cerebrocrast did not alter current kinetics in either investigated channel, and the inhibition of calcium current was partly reversible or irreversible. In conclusion, the interaction of cerebrocrast with CaV3.1 lacked the typical characteristics of a state-dependent interaction, and voltage-dependent inhibition of CaV1.2b was consistent with partial interaction with the inactivated state of the channel.
Drígelová
Mária
M
Institute of Molecular Physiology and Genetics, Centre of Excellence for Cardiovascular Research Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava, Slovak Republic.
Tarabová
Bohumila
B
Duburs
Gunars
G
Lacinová
Lubica
L
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004095:Dihydropyridines / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D011994:Recombinant Proteins; C073838:2,6-dimethyl-3,5-bis(2'-propoxyethoxycarbonyl)-4-(2''-difluoromethoxyphenyl)-1,4-dihydropyridine