[Molecular mechanism of action of benzodiazepines]

Recently, binding sites with high affinity and high specificity for the benzodiazepines have been discovered in mammalian brain. The affinity of the various benzodiazepines for these sites correlates well with the pharmacological potencies of these drugs. It is mainly for this reason that these binding sites are believed to represent the pharmacologically relevant "benzodiazepine receptors". Investigation of the binding of prazepam and metabolites to benzodiazepine receptors in rat brain homogenates reveals that prazepam has only a weak affinity to the receptor(s) with a KD of 1 microM. Its metabolite, descyclopropylmethyl-prazepam (= norprazepam) binds about 100 times more strongly (KD congruent to 15 nM). This shows that norprazepam which is the main pharmacokinetic metabolite (greater than 80% of all metabolites in plasma after oral administration of prazepam) is at the same time the biochemically active substance. Hydroxylation of the 7-membered ring of prazepam or norprazepam in position 3 does not lead to a marked increase in affinity. There is strong electrophysiological and biochemical evidence that the benzodiazepines potentiate GABAergic mechanisms in the CNS (GABA is the major inhibitory transmitter in brain). The molecular events by which the benzodiazepines modulate the GABA system are, however, completely unknown. Also, we do not know whether all pharmacological actions of the benzodiazepines (e.g. anxiolytic action, sedation, muscle relaxation) may be explained by the GABA-hypothesis. The existence of an endogenous substance--which binds to the benzodiazepine receptors--is still open to debate.