ENANTIOSELECTIVE SYNTHESIS OF CYCLOTHIAZIDE ANALOGS - NOVEL PROBES OFTHE STEREOSPECIFIC ACTIONS OF BENZOTHIADIAZINES AT AMPA-TYPE GLUTAMATE RECEPTORS

The stereospecific interactions of the eight stereoisomers of dihydrom ethylcyclothiazide, an analogue of cyclothiazide, with AMPA-type gluta mate receptors was investigated using electrophysiological methods tha t measured the ability of each stereoisomer to inhibit AMPA receptor d esensitization. The eight stereoisomers were obtained by HPLC separati on of four pairs of enantiomerically pure (>95% ee) diastereomers prep ared from (1R-exo)-, (1R-endo)-, (1S-exo)-, and do)-2-methylbicyclo[2. 2.1]heptane-2-carboxaldehyde intermediates. The desensitization proces s was blocked most potently by [1S-[1 alpha,2 alpha(R),4 alpha]]-dihy dromethylcyclothiazide, one of the stereoisomers prepared from the (1S -endo)-carboxaldehyde. The smallest effects on the desensitization pro cess 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 pai rs except those prepared from the (1S-exo)-carboxaldehyde.