Benzodiazepines agonists

TABLE 29-1. Pagoclone versus full agonist benzodiazepines ... 

FIGURE 8-26. The benzodiazepine (BZ) receptor antagonist flumazanil is able to reverse a full agonist benzodiazepine acting at the benzodiazepine receptor of the GABA A receptor complex. This may be helpful in reversing the sedative effects of full agonist benzodiazepines when administered for aesthetic purposes or when taken in an overdose by a patient. 

If a full agonist benzodiazepine reduces anxiety, it would follow that an inverse agonist benzodiazepine would actually produce anxiety. 

A variety of pharmaceutical drugs or intermediates, such as -blockers, P-agonists, benzodiazepines, nonsteroidal anti-inflammatory drugs, and sulfoxides, can be enantioresolved on the same polysaccharide CSP in all HPLC separation modes and in SFC. A common structural feature of these compounds is that they all contain at least one aromatic group and multiple hydrogen-binding sites in... 

The task of the study presented here was to separate a data set of 172 molecules into benzodiazepine agonists 60 compounds) and dopamine agonists (112 compounds) [84]. 

Figure 10.4-7. Representative 2D structures of dopamine and benzodiazepine agonists.

Figure 10.4-S. Kohonen map (10 / 7) obtained from a data set of 112 dopamine and 60 benzodiazepine agonists.

Figure 10.4-9. Kohonen map (40 / 30) of a data set consisting of the dopamine and benzodiazepine agonists of Figure 10.4-8 and 8323 compounds in a chemical supplier s catalog.

Even in this fiiirly diverse data set of structures, the dopamine and benzodiazepine agonists could be separated quite well only two neurons had collisions between these two types ol compounds. Even more importantly, however, we now know in which chemical space one would have to search For new lead structures for dopamine or for benzodiazepine agonists. 

Y C, M G Bures, A A Danaher, J DeLazzer, I Lico and P A Pavlik 1993. A Fast New Approach to irmacophore Mapping and its Application to Dopaminergic and Benzodiazepine Agonists. mal of Computer-A ided Molecular Design 7 83-102. 

Benzodiazepines, ie, the hiU BZR agonists, are prescribed for anxiety, insomnia, sedation, myorelaxation, and as anticonvulsants (97). Those benzodiazepines most commonly prescribed for the treatment of anxiety disorders are lorazepam (19), alprazolam (20), diazepam (21), bromazepam (22), chlorazepate (23), and oxazepam (24). These dmgs together represent about 70% of total... 

YC Martin, MG Bures, EA Danaher, I DeLazzer, I Lico, PA Pavlik. A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists. I Comput Aided Mol Des 7 83-102, 1993. 

Anxiolytics are drugs used for the treatment of anxiety disorders. Apart from benzodiazpines, a frequently used anxiolytic is the 5HT1A (serotonin) receptor agonist buspiron, which has no sedative, amnestic or muscle-relaxant side effects, but whose action takes about a week to develop. Furthermore, it is less efficaceous than the benzodiazepines. Buspiron s mechanism of action is not fully understood. 

Although flumazenil binds with high affinity to the benzodiazepine site of GABAa receptors, it has practically no action when given alone. However, flumazenil competitively blocks the action of benzodiazepine site agonists. Flumazenil can be used to terminate the action of benzodiazepines, e.g., after a benzodiazepine overdose. It may also serve as a diagnostic tool in this regard. 

The binding site for barbiturates on the GABAa receptor is less well defined. Barbiturates act by increasing the conductance level. In contrast to benzodiazepines, they also display direct agonistic action on GABAa receptors. Also in contrast to... 

A medication that causes induction of sleep. The majority of currently available hypnotics (for example benzodiazepine receptor agonists) act via potentiating the brain s inhibitory GABAergic systems, in turn reducing the activity of arousal (i.e. wake promoting) neurotransmitter systems. 

Control of early withdrawal symptoms, which prevents their progression to more serious symptoms, is the indication for which medications are most widely prescribed in the treatment of alcohol dependence. The most commonly used agents to treat alcohol withdrawal are the benzodiazepines, a class of drugs that, by virtue of their agonist activity at the GABA receptor complex, suppress the hyperexcitability associated with alcohol withdrawal. With widespread use of anticonvulsant medications for bipolar disorder and other disorders associated with behavioral disinhibition and CNS hyperexcitability, anticonvulsants have also been examined for use in the treatment of alcohol withdrawal. 

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

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