Pharmacology and Drug Discovery for T-Type Calcium Channels

Abstract

Voltage-gated calcium channels are found in the plasma membrane of many excitable and non-excitable cells. When open, they permit influx of calcium, which acts as a second messenger to initiate diverse physiological cellular processes. Ten unique alpha1 subunits, grouped in three families (CaV1, CaV2, and CaV3), encode biophysically and pharmacologically distinct low-voltage-activated T-type and high-voltage-activated L-type, N-type, P/Q-type, and R-type calcium channels. T-type calcium channels are found in neurons where they generate low-threshold calcium spikes and influence action potential firing patterns, in heart cells where they influence pacemaking and impulse conduction, in smooth muscle cells where they regulate myogenic tone and proliferation, in endocrine cells where they regulate hormone secretion, and in sperm where they regulate the acrosome reaction. Validation of T-type calcium channels in disease is based on an abundance of data pertaining to clinical efficacy of T-type calcium channel blockers in certain human conditions as well as information relating to the distribution, functional properties, and physiological roles of these channels. This review focuses on the cellular and molecular pharmacology of T-type calcium channels. It describes novel research approaches to discover potent and selective T-type calcium channel modulators as potential drugs for treating human disease and as tools for understanding better the physiological roles of T-type calcium channels.

Multi-Functional 3,4-Dihydroquinazoline Derivative as T-Type Calcium Channel Blocker: Pharmacokinetics and Anti-Tremor Activity

“…[1][2][3] Unfortunately, none of these compounds has high selectivity for these channels. Mibefradil has been marketed worldwide for the treatment of hypertension and angina for a short period before it was withdrawn due to its pharmacokinetic and pharmacodynamic interactions with some other drugs such as terfenadine, astemizole, cisapride, cyclosporine, tricyclic antidepressants.…”

Combined L-/T-Type Calcium Channel Blockers

“…3,4 T-type Ca 2ϩ channels are found in various cell types, including neurons, cardiomyocytes, vascular smooth muscle cells, and endocrine cells, where they participate in a variety of physiological processes, such as low-threshold Ca 2ϩ spike generation, action potential firing, pacemaking, impulse conduction, maintenance of myogenic tone, cell proliferation, and hormone secretion. 1 In addition to their predominant role in the regulation of vascular function, T-type Ca 2ϩ channels are also involved in cardiomyocyte growth and survival. 3 T-type Ca 2ϩ channel blockers are capable of interrupting certain pathological hypertrophic signaling pathways, including calcineurin-mediated nuclear factor of activated T cells-3 activation.…”

“…3 T-type Ca 2ϩ channel blockers are capable of interrupting certain pathological hypertrophic signaling pathways, including calcineurin-mediated nuclear factor of activated T cells-3 activation. 1 The importance of voltage-dependent Ca 2ϩ channels is demonstrated by the clinical efficacy of Ca 2ϩ channels blockers in certain disease conditions, as well as the widespread distribution and function of these channels. 1 Three classes of chemically distinct L-type Ca 2ϩ channel blockers have been widely used clinically depending on their biophysical and conformation-dependent interactions with the L-type Ca 2ϩ channel.…”

“…1 The importance of voltage-dependent Ca 2ϩ channels is demonstrated by the clinical efficacy of Ca 2ϩ channels blockers in certain disease conditions, as well as the widespread distribution and function of these channels. 1 Three classes of chemically distinct L-type Ca 2ϩ channel blockers have been widely used clinically depending on their biophysical and conformation-dependent interactions with the L-type Ca 2ϩ channel. These 3 classes include the dihydropyridine, the phenylalkylamine (verapamil), and the benzothiazepine (diltiazem).…”

“…The newly developed dihydropyridine Ca 2ϩ channel blockers, including manidipine, nilvadipine, benidipine, and efonidipine, as well as the benzimidazole mibefradil, appear to possess vasodilatory properties other than blockade of L-type Ca 2ϩ channels. 1,4 These Ca 2ϩ channel blockers may antagonize both L-and T-type Ca 2ϩ channels, which possibly underlie their excellent clinical profiles, such as minimum reflex tachycardia and renal protection. Nonetheless, controversy still exists with regard to the precise role of T-type Ca 2ϩ channels in the regulation of vascular tone.…”