Benzodiazepines produce most, if not all, of their numerous effects on the central nervous system (CNS) primarily by increasing the function of those chemical synapses that use gamma-amino butyric acid (GABA) as transmitter. This specific enhancing effect on GABAergic synaptic inhibition is initiated by the interaction of benzodiazepines with membrane proteins of certain central neurones, to which drugs of this chemical class bind with high affinity and specificity. The molecular processes triggered by the interaction of these drugs with central benzodiazepine receptors, and which result in facilitation of GABAergic transmission, are still incompletely understood. Theoretically, benzodiazepines could mimic the effect of hypothetical endogenous ligands for the benzodiazepine receptors, although there is no convincing evidence for their existence; in vitro studies indicate that benzodiazepines might compete with a modulatory peptide which is present in the supramolecular assembly formed by GABA receptor, chloride ionophore and benzodiazepine receptor and which reduces the affinity of the GABA receptor for its physiological ligand. The mechanisms of action of benzodiazepines at the molecular level are likely to be better understood following our recent discovery of benzodiazepine derivatives, whose unique pharmacological activity is to prevent or abolish in a highly selective manner at the receptor level all the characteristic centrally mediated effects of active benzodiazepines. Here, we describe the main properties of a representative of this novel class of specific benzodiazepine antagonists.

In neurological and behavioral studies in mice, rats, dogs and squirrel monkeys, the imidazobenzodiazepinone Ro 15-1788 acted as a potent benzodiazepine antagonist. The antagonistic activity was both preventive and curative and seen at doses at which no intrinsic effects were detected. It was highly selective in that it acted against CNS effects induced by benzodiazepines but not against those produced by other depressants, such as phenobarbitone, meprobamate, ethanol, and valproate. The onset of action was rapid even after oral administration. Depending on the animal species studied, the antagonistic effects lasted from a few hours to 1 day. The acute and subacute toxicity of Ro 15-1788 was found to be very low. Benzodiazepine-like effects were not seen.

The potent benzodiazepine receptor ligands beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) and the corresponding methylester (beta-CCM) administered i.v. depressed segmental dorsal root potentials in spinal cats, reversed the prolongation of dorsal root potentials by phenobarbitone, and abolished the depression of a motor performance task induced by phenobarbitone in mice; beta-CCE enhanced the low-frequency facilitation of pyramidal population spikes in the hippocampus of anaesthetized rats. These effects of beta-carbolines reflect a depression of GABAergic synaptic transmission and, thus, are diametrically opposed to the enhancing action of benzodiazepine tranquilizers. The specific benzodiazepine antagonist, Ro 15-1788, while not affecting dorsal root potentials, hippocampal population spikes or phenobarbitone-induced motor performance depression, abolished the effects of beta-CCE on the three parameters and similar effects of beta-CCM on the spinal cord and motor performance. A three-state model of the benzodiazepine receptor is proposed in which benzodiazepine tranquilizers act as agonists enhancing the function of the benzodiazepine receptor as a coupling unit between GABA receptor and chloride channel, beta-carbolines act as "inverse agonists" reducing this coupling function, and Ro 15-1788 represents a competitive antagonist blocking both the enhancing effect of agonists and the depressant effect of "inverse agonists" on GABAergic synaptic transmission.

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The combinations of benserazide and levodopa (1:4, Madopar®) and of carbidopa and levodopa (1:10 and 1:4, Sinemet®) are currently the most effective treatment of Parkinson’s disease. In the present comparative study some effects of the peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors benserazide and carbidopa administered alone or in combination with levodopa by the oral route were investigated in two animal species (rat and mouse) and in healthy volunteers. Benserazide is about 10 times more potent than carbidopa as inhibitor of peripheral AADC both in animals and man. Even at relatively high doses (up to 60 µmol/kg p.o.) benserazide is shown in animals to inhibit the decarboxylation of levodopa only in the extracerebral tissues, thus permitting the formation of dopamine in the striatum and in the hypothalamus. As benserazide is the most potent peripheral AADC inhibitor presently available, is well tolerated and relatively nontoxic even when used chronically, it appears to be the peripheral AADC inhibitor of choice for the development of con-trolled-release formulations in which Dopa is combined with a peripheral AADC inhibitor. When administered to healthy subjects the pharmacokinetics of the new drug delivery system named Madopar HBS (hydrodynamically balanced system) was characterized by lower and delayed plasma peak concentrations but a longer-lasting concentration of Dopa than after Madopar standard. Therefore, this new controlled-release system may reduce the clinical fluctuations occurring in patients with ‘wearing-off’ and ‘on-off’ phenomena.

Several benzodiazepines (chlordiazepoxide, clonazepam, diazepam and flunitrazepam) markedly counteracted the elevation of the homovanillic acid (HVA) content of the rat brain induced by neuroleptics (haloperidol, pimozide, chlorpromazine, and clozapine). A similar effect was obtained with the inhibitor of GABA transaminase, aminooxyacetic acid (AOAA). The interaction of benzodiazepines with the neuroleptic-induced HVA increase was similar in the striatum and in the limbic forebrain and was antagonized by the GABA receptor-blocking agent, picrotoxin. Both the benzodiazepines used and AOAA potentiated the cataleptic effect of the four neuroleptics. It is concluded that benzodiazepines, by intensifying GABA-ergic transmission, enhance the ongoing inhibition of mesencephalic dopamine neurons exerted by the striatonigral GABA system. As a consequence, the feedback activation of dopamine neurons induced by the neuroleptic blockade of dopamine receptors in the striatum and the limbic system is attenuated. This results in a reduction of the neuroleptic-induced increase of HVA and in the potentiation of the cataleptic effect of neuroleptics.