Enantioselective synthesis of cyclothiazide analogues: Novel probes of the stereospecific actions of benzothiadiazines at AMPA-type glutamate receptors

The stereospecific interactions of the eight stereoisomers of dihydromethylcyclothiazide, an analogue of cyclothiazide, with AMPA-type glutamate receptors was investigated using electrophysiological methods that measured the ability of each stereoisomer to inhibit AMPA receptor desensitization. The eight stereoisomers were obtained by HPLC separation of four pairs of enantiomerically pure (>95% ee) diastereomers prepared from (1R-exo)-, (1R-endo)-, (1S-exo)-, and (1S-endo)-2-methylbicyclo[2.2.1]heptane-2-carboxaldehyde intermediates. The desensitization process was blocked most potently by [1S-[1 alpha,2 alpha(R*),4 alpha]]-dihydromethylcyclothiazide, one of the stereoisomers prepared from the (1S-endo)-carboxaldehyde. The smallest effects on the desensitization process were found for the four stereoisomers prepared from the (1R-exo)- and (1R-endo)-carboxaldehydes. Significant differences in the ability to inhibit desensitization were observed between all diastereomer pairs except those prepared from the (1S-exo)-carboxaldehyde.