Synthesis, anti-GABA activity and preferred conformation of bicuculline and norbicuculline enantiomers

J. Kardos, T. Blandl, N. D. Luyen, G. Dörnyei, E. Gács-Baitz, M. Simonyi, D. J. Cash, G. Blaskó, Cs Szántay

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10 Citations (Scopus)

Abstract

Synthesis of erythro-(±)-[1SR,9RS]-norbicuculline and threo-(±)-[1SR,9SR]-noradlumidine from piperonal was performed using Bischler-Napieralski cyclization as a key step. Resolution gave rise to (+)-[1S,9R]-norbicuculline ([1S,9R] norBIC) and (-)-[1R,9S]-norbicuculline ([1R,9S] norBIC) in >99.5% enantiomeric purity. Bicuculline enantiomers were readily obtained by methylation of the latter products. [1S,9R]BIC was about 70 times more potent than [1R,9S]BIC as an inhibitor of GABA(A) 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 36Cl- ion flux. The observed increase of about two orders of magnitude in the in vitro biological activity caused by N2-CH3 substitution in [1S,9R] norBIC was attributed to different conformations for erythro- and nor-erythro-bicucullines indicated by 1H nuclear Overhauser enhancements of [1S,9R]BIC and [1S,9R] norBIC.

Original languageEnglish
Pages (from-to)761-765
Number of pages5
JournalEuropean Journal of Medicinal Chemistry
Volume31
Issue number10
DOIs
Publication statusPublished - Jan 1 1996

Keywords

  • Bicuculline enantiomer
  • Bischler-Napieralski cyclization
  • Cl ion flux
  • H nuclear Overhauser enhancement
  • Norbicuculline enantiomer
  • [H]GABA binding

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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