Identification of Binding Sites for Calcium Channel Antagonists.

Abstract

SUMMARYThe binding sites of three typical calcium channel antagonists, 1,4-dihydropyridines, benzothiazepines and phenylalkylamines, were successfully identified within the primary structures of calcium channels using a photoaffinity labeling technique. The results confirm pharmacological observations of the three antagonists that had been proposed to interact allosterically with each other. We briefly review the results and discuss the future prospects. (Jpn Heart J 1996; 37: 643-650)

Design, Synthesis and Calcium Channel Blocking Activity of Diltiazem- Verapamil Hybrid Molecules

“…In contrast, the increase of the incubation time from 10-minute to 2-hour in case of verapamil resulted in an almost 5-fold decrease in the IC 50 value. These results confirm earlier reports that diltiazem binding domains are mainly located close to outer side of the membrane, and that of verapamil more to the interior side [10][11][12][13][14][15]. Table 1 depicts that the hybrid compounds possess dual binding to the membrane domains of both diltiazem and verapamil.…”

“…The design of the current hybrid molecules was prompted by earlier reports that diltiazem binds to calcium channels at a transmembrane region near the extracellular surface, while verapamil binds to a region located toward the intracellular side of the membrane [11][12][13][14][15]. In search of newer CCB with dual affinity to both diltiazem and verapamil binding domains, we designed four hybrid molecules combining important pharmacophores of both drugs, with the ultimate goal to generate compounds with higher activity than the parent drugs.…”

L-Type Voltage-Dependent Calcium Channel Antagonists Impair Perirhinal Long-Term Recognition Memory and Plasticity Processes

“…For systemic administration and in vitro experiments, the chosen single doses of the antagonists were similar to the ones used by previous authors (Morgan and Teyler, 1999;Borroni et al, 2000;Freir and Herron, 2003;Niikura et al, 2004;Woodside et al, 2004), which correspond to dose levels at which the actions of the drugs are likely to be mainly on L-type VDCCs; at higher concentrations, actions have been reported on potassium channels and nicotinic receptors (Hume, 1985;Zhang et al, 1999;Houlihan et al, 2000;Madeja et al, 2000). That the same pattern of memory impairment was seen with exemplars of all three groups of antagonists, which bind to different regions of the channel (Striessnig et al, 1990Nakayama et al, 1991;Nakayama and Kuniyasu, 1996;Hockerman et al, 2000), adds weight to the conclusion that the effects of the drugs are attributable to antagonism of L-type VDCCs. The parallel results produced by the localized infusion of verapamil establish that an action within the PRH region is sufficient to produce memory impairment.…”

“…As a check for specificity of action, we tested the effects on memory of an exemplar of each of the three main types of L-type VDCC antagonists-phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), and dihydropyridines (e.g., nifedipine)-as they have different chemical structures and bind at different sites on the channels (Striessnig et al, 1990Nakayama et al, 1991;Nakayama and Kuniyasu, 1996;Hockerman et al, 2000).…”

Photochemical localization of the semotiadil binding region within the cardiac Ca2+ channel α1 subunit. Comparison with the skeletal muscle counterpart

“…Ca 2+ antagonists bind to L‐type Ca 2+ channels and block the entry of extracellular Ca 2+ . Three classes of Ca 2+ antagonists, 1,4‐dihydropyridines (DHP), phenylalkylamines (PAA) and benzothiazepines (BTZ), bind to different regions on the α1 subunit of Ca 2+ channels [1, 2]as shown by photoaffinity labeling and molecular biological studies. As to the DHP binding site, not only transmembrane segment IVS6 but also IIIS6 and IIIS5 have been identified as molecular determinants of binding [3–8].…”