SYNTHESIS, ANTI-GABA ACTIVITY AND PREFERRED CONFORMATION OF BICUCULLINE AND NORBICUCULLINE ENANTIOMERS

Synthesis of erythro-(+/-)-[1SR,9RS]-norbicuculline and threo-(+/-)-[1 SR,9SR]-noradlumidine from piperonal was performed using Bischler-Napi eralski cyclization as a key step. Resolution gave rise to (+)-[1S,9R] -norbicuculline ([1S,9R] norBIC) and (-)-[1R,9S]-norbicuculline ([1R,9 S] norBIC) in >99.5% enantiomeric purity. Bicuculline enantiomers were readily obtained by methylation of the latter products. [1S,9R] BIC w as about 70 times more potent than [1R,9S] BIC as an inhbitor of GABA, receptor binding and was about 100 and 900 times more potent than [1S ,9R] norBIC at pH 7.1 and 5.0 respectively. Similarly, [1S,9R] norBIC was much less potent than [1S,9R] BIC as an inhibitor of GABA-specific Cl-36(-) ion flux. The observed increase of about two orders of magni tude in the in vitro biological activity caused by N2-CH3, substitutio n in [1S,9R] norBIC was attributed to different conformations for eryt hro- and nor-erythro-bicucullines indicated by H-1 nuclear Overhauser enhancements of [1S,9R] BIC and [1S,9R] norBIC.