THE SYNTHESIS OF 2-CYCLOHEXYLIDENEPERHYDRO-4,7-METHANOINDENES - NONSTEROIDAL ANALOGS OF STEROIDAL GABA(A) RECEPTOR MODULATORS

Racemic (3a alpha,4 beta,7 beta,7a alpha)-2-cyclohexylideneperhydro-4, 7-methanoindene derivatives (+/-)-3 and (+/-)-4 were synthesised as an alogues of steroidal GABA(A) receptor modulators 1 and 2 respectively. The lithium dianion generated from epimeric ,7,7a-hexahydro-4,7-metha no-1H-indene-2-carboxylic acids, 8 and 9, reacted with a commercially available cyclohexanone to generate P-hydroxy carboxylic acids. Cyclod ehydration to P-lactones followed by the thermal elimination of carbon dioxide gave a suitably functionalised 2-cyclohexylidenehexahydro-4,7 -methano-1H-indene derivative 18. Regio- and stereospecific hydrocyana tion of the bicyclo[2.2.1]hept-2-ene moiety of 18 was achieved via hyd roboration affording a racemic nitrile, 19. This underwent further tra nsformations to give (+/-)-3 and (+/-)-4 and their hydroxy group epime rs (+/-)-5 and (+/-)-6 respectively. X-Ray structure data was obtained for ()-3. The effects of compounds (+/-)-3-(+/-)-6 on the binding of the GABA(A) receptor agonist [H-3]muscimol to rat synaptic membranes w ere measured. Compound (+/-)-4 was a weak positive modulator while the others were inactive.