Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non–L-type channels have not been found. The underlying reasons for this are discussed together with suggestions for new directions, including fertility control, oxygen-sensitive channels, and calcium channel activators.