Pharmacological modulation of Cl -channels

The receptor-operated Cl -channels of the central nervous system (CNS) are gated by the respective agonists GABA and glycine. Most Cl -channels can be inhibited by disulphonate stilbenes. Muscle Cl -channels can be inhibited by anthracene-9-carboxylate (A9C) and probably by IAA-94. The ICOR Cl -channel is fairly sensitive to NPPB. It should be noted, however, that none of these probes, except for the GABA- and glycine-receptor Cl -channels, is of sufficient affinity and selectivity to permit the channel identification by its use. This dilemma is one of the reasons why the purification of epithelial Cl -channels lags behind that of the CNS Cl -channels. 

Pharmacological modulation of GABA -receptor and glycine-receptor channels 

This area has been covered in a review by Eldefrawi and Eldefrawi [23]. The GABA -receptor channel is activated by GABA (Fig. 2), avermectin, muscimol, taurine (Fig. 2) and j -alanine (Fig. 2). The activation by agonists is potentiated by benzodiazepines and barbiturates. The channel is blocked by the competitive 

Other blockers of epithelial Cl -channels are of the aryl-amino-benzoate type or phenoxy-acetic-acid type [70]. Very few systematic surveys comparing different classes of blockers in one type of Cl -channel are available at this stage. One such study has been performed in membrane vesicles from kidney cortex [80]. In this study IAA-94 and NPPB (cf. Fig. 2) turned out to be the most potent blocker of conductive Cl -flux. In another systematic survey the Cl -conductance of the sweat duct was examined, and it was found that dichloro-DPC (Fig. 2) was the most potent inhibitor of the transepithelial Cl -conductance [90]. 

Several studies have been performed in the laboratory of my colleagues and I [41,70,91-93]. In one of these, starting with the structure of A9C (Fig. 2), the inhibitory effect on the Cl -conductance in thick ascending limb (TAL) segments has been examined. It was found that DPC was much more potent than A9C [41]. In a subsequent study on the same preparation more than 100 relatives of DPC 

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