Benzodiazepine receptor site

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

The activity of benzodiazepines may be terminated when the drug is removed from the benzodiazepine receptor site and diffuses into peripheral adipose tissue sites and then metabolized in the liver, or when there is a decrease in the sensitivity of the benzodiazepine receptors following chronic exposure to the drug (termed acute tolerance). The rate of development of acute tolerance appears to vary with the different benzodiazepines, making it difficult to relate the changes in therapeutic response to the changes in plasma concentration. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

Pharmacology Benzodiazepines appear to potentiate the effects of gamma-aminobutyrate (GABA) (ie, they facilitate inhibitory GABA neurotransmission) and other inhibitory transmitters by binding to specific benzodiazepine receptor sites. 

Other than adenosine, there are several peptides which induce sleep (e.g., delta sleep inducing peptide). Together with endogenous chemicals interacting with the GABA benzodiazepine receptor site (e.g., (3-carbolines) identified in... 

Mechanism of Action A benzodiazepine that depresses all levels of the CNS, includ-ing limbic and reticular formation, by binding to benzodiazepine receptor sites on the gamma-aminobutyric acid (GABA) receptor complex. Modulates GABA, a major inhibitory neurotransmitter in the brain. Therapeutic Effect Produces anxiolytic effect,... 

Now it is probably no coincidence that in addition to occupying the benzodiazepine receptor site on the chloride ion channel protein, these remarkable drugs can also occupy the sedation-convulsant receptor of the same protein. Sedation with benzodiazepines thus goes hand in hand with anticonvulsant power—as if the two processes had some deep mediating mechanism in common with each other. What could that be ... 

Several new anxiolytic and sedative drugs act at the benzodiazepine receptor site, or one of the subsets that comprise this receptor site even though the chemical structure of these molecules differs substantially from the benzodiazepines. One of the first of these compounds to be developed was the cyclopyrrolone zopiclone. A structurally somewhat similar molecule... 

Mode of action. Clobazam, like most of the benzodiazepines in clinical use, acts as an agonist on the benzodiazepine receptor site and thereby enhances GABAergic transmission. It is uncertain why the action of clobazam differs from the conventional benzodiazepines but it is possible that it could reflect differential binding to the GABA-A receptor sub-units. In addition to its action on GABA receptors, clobazam also reduced voltage-sensitive calcium ion conductance and sodium channel conductance. 

There is excessive activity of an endogenous inverse agonist at the benzodiazepine receptor site (see p. 232 for a detailed discussion). 

Three types of endozapines have been isolated. It is known that the beta-carbolines can be synthesized in the mammalian brain and that, in vitro, they act as inverse agonists at benzodiazepine receptor sites. Theoretically such compounds could induce anxiety. However, none of these compounds has been isolated in vivo and the original detection of a beta-carboline in the urine of anxious patients was later found to be an artifact, possibly caused by bacterial contamination. 

Chemical classes other than benzodiazepines bind to, and have actions at the various benzodiazepine receptor sites. Notably, there are P-carbolines that have either agonist or inverse agonist actions, with a corresponding pharmacology similar to. or the opposite of typical benzodiazepines (e.g, anxiolytic or anxiogenic actions) see BENZODIAZEPINE RECEPTOR INVERSE AGONISTS. 

The GABA-receptor complex, the primary inhibitory neural network within the central nervous system, is associated with HE. This receptor complex is composed of a GABA-binding site, and a benzodiazepine receptor site, which mediate chloride conductance. Based on evidence of an increase in benzodiazepine receptor ligands in patients with hepatic encephalopathy, flumazenil has been evaluated in uncontrolled studies and has demonstrated significant clinical improvement, with one case report documenting long-term benefit. In these reports, discontinuation of flumazenil resulted in prompt clinical deterioration. 

G. Greco, E. Novellino, C. Silipo, and A. Vittoria, Quant. Struct.-Act. Relat., 11, 461 (1992). Study of Benzodiazepine Receptor Sites Using a Combined QSAR-CoMFA Approach. 

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