1,4-Dihydropyridines: the multiple personalities of a blockbuster drug family
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More than 40 years after their introduction in therapy, 1,4-dihydropyridines (DHPs) are still amongst the most prescribed drugs in the world. Though they all share a similar mechanism of action blocking L-type voltage-gated Ca2+ channels, DHPs differ in crucial pharmacological properties like tissue selectivity and cardiodepressant activity. This review examines how changes in the DHP structure can modify the pharmacological properties of these drugs and how some of these chemical manipulations have been exploited to obtain clinically more effective molecules. Special emphasis is given to the evidence that L-type Ca2+ channels are an heterogeneous family and that DHPs with different pharmacological properties differ in their affinity for the different isoforms of this class of channels. Data showing that DHP pharmacological heterogeneity could be in part dependent on the interaction of some of these molecules with ion channels different from the L-type Ca2+ channels is reviewed as well.