Peripheral metabolism of beta-carboline-carboxylic acid esters.

Esters of beta-carboline-3-carboxylic acid have recently been identified as potent inhibitors of brain benzodiazepine receptors in vitro. Ethyl beta-carboline-3-carboxylate (beta-CCE), however, is a rather weak inhibitor in vivo of benzodiazepine receptors in mice. The ED50-value was 91 mg/kg intraperitoneally 35 min after administration (ED50 is that dose which inhibits by 50% the specific binding of 3H-flunitrazepam intravenously). ED50 for beta-CCE was 2-20 fold lower in mice pretreated with organophosphorus esterase inhibitors, concomitantly with the observation of strong inhibition of liver and kidney hydrolyzing activity, using 3H-propyl beta-carboline-3-carboxylate as substrate. The rat brain contains only approximately 0.1% of the hydrolyzing activity as compared to the liver. It is concluded that some esters of beta-carboline-3-carboxylate exhibit only weak effects on benzodiazepine receptors in living animals due to hydrolysis outside the brain.