Clinical perspectives of β-carbolines from first studies in humans

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First results from studies in healthy subjects with the β-carbolines ZK 91 296, ZK 95 962 and ZK 93 426 are reviewed. ZK 91 296 and ZK 95 962, characterized as partial benzodiazepine agonists in preclinical research, were unable to induce some typical benzodiazepine effects like sedation when administered intravenously in high doses. ZK 95 962, reported to be effective in photoepileptic patients, was able to reverse lormetazepam-induced sleep as documented by EEG-parameters. The benzodiazepine receptor antagonist ZK 93 426 dose-dependently elicited alertness, restlessness and mild apprehension—symptoms opposite those known for the benzodiazepines. The activating effect of ZK 93 426 was confirmed by the results from, e.g., self-rating scales and the logical reasoning test. In another placebo-controlled study comparing the effects of ZK 93 426 alone and in combination with lormetazepam vigilosomnograms obtained after ZK 93 426 alone clearly confirmed the activating effect. In combination with lormetazepam ZK 93 426 was able to reverse the benzodiazepine induced sleep. The attenuation of benzodiazepine effects was also evident from multiple sleep latency tests. Our results support findings from animal experiments which classify these β-carbolines as benzodiazepine receptor ligands with partial agonist and antagonist properties. β-Carbolines may prove to be beneficial drugs in the treatment of anxiety, convulsions and diseases with an impairment of cognitive functions as well as in the reversal of unwanted benzodiazepine effects.