New developments in calcium ion channel antagonists

Abstract

Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.

7-Chloro-3-methyl-3,4-dihydro-2 H -1,2,4-benzothiadiazine S , S -dioxide: A partial modulator of AMPA receptor desensitization devoid of neurotoxicity

“…The increase in the [Ca 2ϩ ] i transient elicited by combined AMPA͞IDRA-21 (Fig. 3) or AMPA͞cyclothiazide treatments (data not shown) were also considerably reduced by nitrendipine, a blocker of L-type-voltage-sensitive calcium channels (VSCC) (27). Such nitrendipine pretreatment also reduced by Ϸ50% the neuronal death induced by 25 (Fig.…”

“…We observed that the [Ca 2ϩ ] i transient but not the [Na ϩ ] i transient increase elicited by application of AMPA͞IDRA-21 is reduced (by 60-70%) when the cells are exposed to the blocker of VSCC nitrendipine (27). At a dose of 1 M, nitrendipine reduces by Ϸ50% AMPA plus cyclothiazide-induced neurotoxicity, suggesting that the time-course of the [Ca 2ϩ ] i transient increase elicited by application of AMPA͞IDRA-21 or AMPA͞ cyclothiazide is at least in part indirectly mediated by the opening of L-type VSCC triggered by the neuronal depolarization caused by a Na ϩ influx occurring via AMPA receptor activation.…”

Change in Swimming Behavior ofTetrahymena pyriformisMediated by Calcium-function Modulating Compounds

“…Dot-like traces show the cells with only active rotation. Among the calcium channel blockers, cinnarizine and nicardipine 15 ) induced the change in swimming behavior. As in the case of the calmodulin antagonists, the cells swam forwards again after a few more minutes of incubation.…”

Anti-dihydropyridine Antibodies Exhibit [3H]Nitrendipine Binding Properties Similar to the Membrane Receptor for the 1,4-Dihydropyridine Ca2+ Channel Antagonists

“…Drugs that block these voltagedependent Ca 2+ channels are used for the treatment of various cardiovascular disorders and are referred to as Ca 2+ channel antagonists (4)(5)(6)(7)(8). Nifedipine, nitrendipine, nisoldipine, and related 1,4-dihydropyridines are the most potent class of Ca 2+ channel antagonists, and radiolabeled dihydropyridines have been shown to bind with high affinity to membranes isolated from cardiac, skeletal, and smooth muscle (9)(10)(11)(12)(13).…”