Central nervous system molecular agents

The present chapter will address the following issues (1) a very brief overview on the properties of the different types of Cl -channels in the various mammalian cells (2) a short summary on what is known of Cl channels on a molecular basis (3) a discussion of pharmacological agents blocking the various Cl -channels and (4) a specific section dealing with the regulation of epithelial and maybe other Cl -channels. This entire area has been reviewed rather extensively in the recent past. A large number of references will be provided in order to keep this text concise. The entire field of Cl -channels in the central nervous system will only be touched upon to compare these channels to the Cl -channels in apolar cells and epithelia. 

The clinical effects of chloroform toxicity on the central nervous system are well documented. However, the molecular mechanism of action is not well understood. It has been postulated that anesthetics induce their action at a cell-membrane level due to lipid solubility. The lipid-disordering effect of chloroform and other anesthetics on membrane lipids was increased by gangliosides (Harris and Groh 1985), which may explain why the outer leaflet of the lipid bilayer of neuronal membranes, which has a large ganglioside content, is unusually sensitive to anesthetic agents. Anesthetics may affect calcium-dependent potassium conductance in the central nervous system (Caldwell and Harris 1985). The blockage of potassium conductance by chloroform and other anesthetics resulted in depolarization of squid axon (Haydon et al. 1988). 

While Via antagonists have been synthesized, none of these have been reported to penetrate the central nervous system efficiently. In 2007, the same authors have identified the azetidinone LY307174 (I, Fig. 39), for a screening based on 59% molecular similarity to ketoconazole (II, Fig. 39), a marketed antifungal agent... 

Nicholls, I.A., Craik, D.J. and Alewood, P.F. (1994) NMR and molecular modelling based conformational analysis of some N-alkyl l-and 2-benzazepinones useful central nervous system agent design motifs. Biochem. Biophys. Res. Comm. 205 98-104. 

The newest antifungals, the echinocandins, are macromolecular structures with high molecular weights (>1,000 dalton), which a student can easily visualize by looking at the chemical structure. Their relatively low volume of distribution in the body can be partially explained by their size. Clinically, these agents have not achieved high concentrations in the central nervous system and the vitreous chamber of the eye, two compartments that are subject to fungal invasion. 

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