Institute of Molecular Physiology and Genetics, Centre of Excellence for Cardiovascular Research Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava, Slovak Republic.
Can J Physiol Pharmacol. 2009 Nov;87(11):923-32. doi: 10.1139/y09-086.
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.
Cerebrocrast 是一种新型亲脂性二氢吡啶衍生物，具有潜在的神经保护和抗糖尿病特性。我们使用全细胞膜片钳技术在 HEK 293 细胞中分析了它与 L 型（CaV1.2b）和 T 型（CaV3.1）钙通道的相互作用。Cerebrocrast 抑制了 CaV1.2b 和 CaV3.1 通道的电流通量。在这两种情况下，该药物的效果比中性二氢吡啶弱约 10 倍，但比带电荷的二氢吡啶氨氯地平更有效。在保持电位为-80 mV 和-50 mV 时，CaV1.2b 通道的 IC50 值分别为 586±96 nmol/L 和 178±78 nmol/L。大约需要 50 μmol/L 的 Cerebrocrast 来阻断 CaV3.1 通道中 50%的电流幅度，但将保持电位从-100 mV 移至-70 mV 并不能促进这种抑制。Cerebrocrast 未改变两种研究通道中的电流动力学，钙电流的抑制部分是可逆的或不可逆的。总之，Cerebrocrast 与 CaV3.1 的相互作用缺乏状态依赖性相互作用的典型特征，而 CaV1.2b 的电压依赖性抑制与通道失活状态的部分相互作用一致。
