BETA-CARBOLINES AS INVERSE AGONISTIC BENZODIAZEPINE RECEPTOR LIGANDS .2. SYNTHESIS AND IN-VITRO AND IN-VIVO BINDING OF SOME NEW 6-AMINO-BETA-CARBOLINE-3-CARBOXYLATES AND 6-FLUORO-BETA-CARBOLINE-3-CARBOXYLATES

Six new 6-fluoro-beta-carboline-3-carboxylates (3a-f) with their relat ed 6-amino analogues (2a-f) are described and their in vitro and in vi vo capabilities to bind to rat cerebral cortex 'benzodiazepine recepto rs' checked by radioreceptor assay (RRA). For some of the derivatives, the tests were also accomplished in the absence and presence of 10 mu M GABA, whereby an inverse agonistic activity resulted. Their IC50 fo r [H-3]flunitrazepam displacement were in the 10(-9)-10(-12) molar ran ge. The same compounds, with the exception of the hydroxylated compoun ds 2e, 2f, 3e and 3f, crossed the blood-brain barrier in the rat, gene rally giving rise to higher concentrations in the brain (ng/g) than in the plasma(ng/ml). The synthetic pathway preferred here allows a rapi d fluorine incorporation in this moiety and an easy isolation of the f luorinated compounds.