Differential pharmacological effects of β-carboline-3-carboxylic acid esters

Abstract

The effects of the methyl, ethyl and propyl esters of β-carboline-3-carboxylic acid have been studied in vitro and in vivo . All three esters were found to be potent inhibitors of 3H-flunitrazepam binding in the rat cerebellum and cerebral cortex in vitro . In vivo , the methyl and ethyl esters were potent proconvulsant agents, whereas the propyl ester was not. Furthermore, the methyl ester produced convulsions which were blocked by the ethyl and propyl esters as well as by diazepam. These in vivo differences may be due to the β-carboline esters having different proportions of agonistic and antagonistic actions at their recognition sites. There is good evidence that the pharmacological actions of benzodiazepines are mediated via specific binding sites found in mammalian brain (Braestrup & Squires, 1978; Mohler & Okada, 1977; Squires & Braestrup, 1977). In an attempt to isolate an endogenous ligand for these receptors, Braestrup, Nielsen & Olsen (1980) discovered ethyl-β-carboline-3-carboxylate (β-CCE) in human urine. This compound, although now known to be an extraction artifact, shows a very high affinity for benzodiazepine receptors (Braestrup, Nielsen and Olsen, 1980: Nielsen & Braestrup, 1980). More recently, β-CCE has been shown to have pharmacological actions opposite to those of the benzodiazepines and can reverse some of their actions (Cowen, Green, Nutt & Martin, 1981; Oakley & Jones 1980; Tenen & Hirsch 1980). In the present study, the pharmacological effects of two closely related β-carbolines, methyl-β-carboline-3-carboxylate (β-CCM) and propyl-β-carboline -3-carboxylate (β-CCP), were investigated.