Peripheral Metabolism of β-Carboline-Carboxylic Acid Esters

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Abstract
Esters of β‐carboline‐3‐carboxylic acid have recently been identified as potent inhibitors of brain benzodiazepine receptors in vitro. Ethyl β‐carboline‐3‐carboxylate (β‐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 β‐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 β‐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 β‐carboline‐3‐carboxylate exhibit only weak effects on benzodiazepine receptors in living animals due to hydrolysis outside the brain.