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H Möhler

Publications and source records attributed to H Möhler.

At least 91 records · Page 5Linked to original sources
PubMed1983

Benzodiazepine receptors: differential ligand interactions and purification of the receptor protein.

The benzodiazepine receptor can be considered as a regulatory unit for GABA receptor function. Receptor agonists such as the classical benzodiazepines induce a conformational change of the receptor which results in an enhancement of GABAergic transmission, leading to therapeutically useful effects. Inverse agonists such as several beta-carboline derivatives induce a different conformational change of the receptor resulting in a reduction of GABAergic transmission with concomitant anxiogenic and convulsant effects. Antagonists like Ro 15-1788 largely lack drug efficacy per se but antagonize the action of agonists and inverse agonists by competitive interaction at the receptor. Highly purified benzodiazepine receptor fractions showed properties similar to those in intact neuronal membranes. The receptor fractions contained high affinity binding sites for benzodiazepine agonists, antagonists and inverse agonists which were amenable to modulation by GABA. In addition, high affinity sites for GABA were present. The progress made in the isolation of the GABA receptor complex raises hopes to determine the molecular details of receptor function and of drug efficacy in the near future.

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PubMed1981

Selective antagonists of benzodiazepines.

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.

Animals↗
PubMed1981

Autoradiographic localization of benzodiazepine receptors in immunocytochemically identified gamma-aminobutyrergic synapses.

Benzodiazepine receptors can be visualized in regions of synaptic contact by electron microscopic autoradiography using [3H]flunitrazepam as a photoaffinity label in fresh brain tissue. Perfusion fixation of the tissue prior to photoaffinity labeling left the ligand binding characteristics and the light and electron microscopic distribution of benzodiazepine receptors unaltered. Therefore, the immunocytochemical localization of a neuronal marker in fixed tissue could be combined with photoaffinity labeling in order to identify the types of synapses containing benzodiazepine receptors. By using antiserum to glutamate decarboxylase, a marker of gamma-aminobutyrergic neurons, one-third of the photolabeled benzodiazepine receptors were found to be associated with immunocytochemically stained nerve endings. Thus, these synapses are the site of at lest some benzodiazepine receptors. The enhancement of gamma-aminobutyrergic synaptic transmission by benzodiazepines, shown electrophysiologically, appears to be a primary mechanism of action of this group of drugs.

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PubMed1981

Benzodiazepine antagonist Ro 15-1788: binding characteristics and interaction with drug-induced changes in dopamine turnover and cerebellar cGMP levels.

The recently discovered benzodiazepine antagonist Ro 15-1788 was characterized in binding studies, and its potency and selectivity were determined in vivo by interaction with drug-induced changes in dopamine turnover and cerebellar cGMP level. Ro 15-1788 reduced [3H]flunitrazepam binding in the brain in vivo with a potency similar to that of diazepam and effectively inhibited [3H]diazepam binding in vitro (IC50 = 2.3 +/- 0.6 nmol/liter). [3H]Ro 15-1788 bound to tissue fractions of rat cerebral cortex with an apparent dissociation (KD) of 1.0 +/- 0.1 nmol/liter. The in vitro potency of various benzodiazepines in displacing [3H]Ro 15-1788 from its binding site was of the same rank order as found previously in [3H]diazepam binding. Autoradiograms of [3H]Ro 15-1788 binding in sections of rat cerebellum showed the same distribution of radioactivity as with [3H]flunitrazepam. The attenuating effect of diazepam on the chlorpromazine- or stress-induced elevation of homovanillic acid in rat brain was antagonized by Ro 15-1788. Among a series of compounds which either decreased or increased the rat cerebellar cGMP level, only the effect of benzodiazepine receptor ligands (diazepam, zopiclone, CL 218 872) was antagonized by Ro 15-1788. Thus, Ro 15-1788 is a selective benzodiazepine antagonist acting at the level of the benzodiazepine receptor in the central nervous system. Peripheral benzodiazepine binding sites in kidney and schistosomes were not affected by Ro 15-1788.

Animals↗
PubMed1981

Pharmacology of midazolam.

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

Anesthetics↗
PubMed1981

Benzodiazepine receptors: autoradiographical and immunocytochemical evidence for their localization in regions of GABAergic synaptic contacts.

The morphological demonstration of BR in GABAergic synapses is a major step forward in the understanding of the mechanism of action of benzodiazepines. It bridges the gap between the electrophysiological evidence stressing the involvement of GABAergic synaptic transmission in the action of benzodiazepines, and the biochemical evidence stressing BR as the site of action for this group of drugs. At present we do not know in which types of synapses those BR are localized which were not associated with GAD positive terminals. At least some of the silver grains may nevertheless be localized in GABAergic terminals, since probably not all GABAergic terminals were stained immunocytochemically. However, it is also possible that some BR are localized in non-GABAergic synaptic contact regions. This possibility would open new concepts for our understanding of the mechanism of action of benzodiazepines and is presently under experimental investigation.

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PubMed1980

Benzodiazepine receptor protein identified and visualized in brain tissue by a photoaffinity label.

Flunitrazepam, a potent benzodiazepine, reversibly binds to the benzodiazepine receptor with high affinity. When irradiated with UV light, flunitrazepam was irreversibly linked to brain tissue. Incorporation of [3H]flunitrazepam was inhibited by other benzodiazepines with a potency corresponding to their affinity for the benzodiazepine receptor. Photolabeling with flunitrazepam reduced the number of benzodiazepine receptors determined by reversible binding of benzodiazepines, whereas the apparent affinity of the remaining receptors was unchanged. Half-maximal incorporation of flunitrazepam occurred at a concentration similar to the apparent dissociation constant of flunitrazepam. Thus, flunitrazepam appears to be a photoaffinity label for the benzodiazepine receptor. The receptor component photolabeled with flunitrazepam was a protein of molecular weight 50,000. Its location in cerebral and cerebellar cortex slices could be visualized by electron microscopic autoradiography. A predominant localization of benzodiazepine receptors in regions of synaptic constants, including those formed by GABAergic neurons (GABA is gamma-aminobutyric acid), was observed.

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