New synthetic ligands for L-type voltage-gated calcium channels

Abstract

The first generation calcium antagonists verapamil, nifedipine and diltiazem (Figure 1), have achieved major prominence for their therapeutic actions in a number of cardiovascular disorders and for their potential roles in a variety of other disorders from achalasia to vertigo (Table 1). These agents and their second generation analogs owe their usefulness to an ability to interact specifically at one locus of cellular calcium regulation — the L-type voltage-gated calcium channel [1,2]. The roles of calcium as a critical mediator serving to link cellular excitation and response are well known [3]. The cell maintains a low resting intracellular concentration of ionized calcium in the face of large and inwardly directed electrochemical and concentration gradients. In the absence of appropriate control calcium plays pathological roles mediating cell destruction and death [4]. Cellular calcium walks the line between physiology and pathology and the control of calcium movements and storage is thus a fundamental preoccupation of the cell. Accordingly, cells possess a number of calcium-regulating processes at both plasmalemmal and intracellular locations (Figure 2). In principle, all of these sites are candidates for interactions with specific categories of drugs.