Structure-Function Studies of Sponge-Derived Compounds on the Cardiac Ca V 3.1 Channel.

T-type calcium (Ca V 3) channels are involved in cardiac automaticity, development, and excitation-contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no Ca V 3 channel inhibitors are used in clinical settings. To identify novel T-type calcium channel ligands, purpurealidin analogs were electrophysiologically investigated. These compounds are alkaloids produced as secondary metabolites by marine sponges, and they exhibit a broad range of biological activities. In this study, we identified the inhibitory effect of purpurealidin I (1) on the rat Ca V 3.1 channel and conducted structure-activity relationship studies by characterizing the interaction of 119 purpurealidin analogs. Next, the mechanism of action of the four most potent analogs was investigated. Analogs 74 , 76 , 79 , and 99 showed a potent inhibition on the Ca V 3.1 channel with IC 50 's at approximately 3 μM. No shift of the activation curve could be observed, suggesting that these compounds act like a pore blocker obstructing the ion flow by binding in the pore region of the Ca V 3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of Ca V 3 channel inhibitors has been discovered and the structure-function studies provide new insights into the synthetic design of drugs and the mechanism of interaction with T-type Ca V channels.