1,5-Benzodiazepine clobazam

Figure 9.2. Chemical structure of some commonly used benzodiazepines. Clobazam differs from the other benzodiazepines shown, being a 1,5- rather than...

Lacroix, C. Wojciechowski, F. Danger, P. Monitoring of benzodiazepines (clobazam, diazepam and their main active metabolites) in human plasma by column-switching high-performance liquid chromatography. J.Chromatogr., 1993, 617, 285-290... 

It is interesting to note that some 1,5-benzodiazepines such as 29 also possess CNS depressant activity. Treatment of substituted diphenylamine 26 with methyl malonyl chloride and reduction with Raney nickel led to orthophenylenediamine analogue 27. Sodium alkoxide treatment led to lactam formation (28), and alkylation in the usual way with NaH and methyl iodide produced clobazam (29). °... 

Parrott AC and Kentridge R (1982). Personal constructs of anxiety under the 1.5-benzodiazepine derivative clobazam, related to trait-anxiety levels of the personality. Psychopharmacology, 78, 353-357. 

The relative contribution of the active metabolites of the benzodiazepines to the overall therapeutic effect of the parent compound will depend on the concentration of the metabolite formed, its agonist potency at central benzodiazepine receptors and its lipophilicity. For example, after the chronic administration of diazepam, desmethyldiazepam accumulates in the brain. As this metabolite has potency at the benzodiazepine receptors equal to diazepam, the metabolite probably plays an important part in the overall action of diazepam. In the case of clobazam, however, even though the active metabolite desmethylclobazam is present in higher concentrations than the parent compound after chronic administration, it has a lower potency than clobazam and therefore is of less importance than the parent compound with regard to the anxiolytic effect. 

Benzodiazepines are the drugs of choice for status epilepticus (see above) however, development of tolerance renders them less suitable for long-term therapy. Clonazepam is used for myoclonic and atonic seizures. Clobazam, a 1,5-benzodiazepine exhibiting an increased anticonvulsant/seda-tive activity ratio, has a similar range of clinical uses. Personality changes and paradoxical excitement are potential side effects. 

Other benzodiazepines have been used as AEDs but are not approved for this use in the United States. They include lorazepam Ativan), nitrazepam Mogadon), and clobazam UrbaniJ). It is unlikely that these drugs offer any advantages over similar agents. 

Clobazam is not available in the USA but is marketed in most countries and is widely used in a variety of seizure types. It is a 1,5-benzodiazepine (other marketed benzodiazepines are 1,4-benzodiazepines) and reportedly has less sedative potential than benzodiazepines marketed in the USA. Whether the drug has significant clinical advantages is not clear. It has a half-life of 18 hours and is effective at dosages of 0.5-1 mg/kg/d. It does interact with some other antiseizure drugs and causes adverse effects typical of the benzodiazepines efficacy, in some patients, is limited by the development of tolerance. 

Benzodiazepines used to treat epilepsy include diazepam, clonazepam, clobazam and lorazepam. Of these, diazepam and lorazepam have been most widely used to control status epilepticus, while use of clonazepam is usually restricted to the chronic treatment of severe mixed types of seizures (e.g. Lennox-Gastaut syndrome and infantile spasm). The major problem with most of the benzodiazepines, with the possible exception of clobazam, is sedation. 

Clonazepam is the most potent of the benzodiazepine anticonvulsants and is particularly indicated in the treatment of the more difficult cases of epilepsy, especially those of the multiple seizure type. More recently, clobazam, which at therapeutic doses has the advantage of causing little... 

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. 

Side effects. Because clobazam has been widely used as an anxiolytic, its side effects are well known and essentially similar to those of the other benzodiazepines. Thus sedation, dizziness, ataxia, blurred vision and diplopia are the most commonly reported in epileptic patients. One of the most problematic features of clobazam is its tendency to produce tolerance, an effect which may occur more frequently with clobazam than with the other widely used benzodiazepine, clonazepam. It has been estimated that at least 50% of patients develop tolerance. Tolerance to the sedative effects of the drug develop more rapidly than those to the antiepileptic effect. Clobazam should be considered as adjunctive therapy whenever treatment with a single first-line drug has proven to be ineffective. 

This fivefold clinical activity is possessed, to a greater or lesser extent, by all benzodiazepines in current clinical use. The properties of benzodiazepines make them ideally useful for managing anxiety (e.g. diazepam, chlordiazepoxide, lorazepam) insomnia (e.g. diazepam, temazepam, nitrazepam, loprazolam, flurazepam, lormetazepam) epilepsy (e.g. clobazam, diazepam, lorazepam) sports injuries where muscle relaxation is required (e.g. diazepam) and as premedications prior to surgery (e.g. midazolam, lorazepam). The benzodiazepines have a number of other uses, including management of alcohol withdrawal syndrome (chlordiazepoxide, diazepam) and restless legs (clonazepam). Short... 

Clobazam, a 1,5-benzodiazepine, differs in its chemical structure from most other benzodiazepines. It has been claimed to have less sedative effects for its effective anticonvulsant and anti-anxiety effects (SED-12, 98). Whether because of tolerance or not, clobazam tends to be less sedative than clonazepam. Both the therapeutic and adverse effects of clobazam have been related to its major metabolite Al-desmethylclobazam, the formation of which depends on CYP2C19 activity. Mutant alleles that confer high CYP2C19 activity, and are therefore associated with high concentrations of the metabolite, are particularly common (30-40%) in Asian populations (1)-... 

Clobazam is better tolerated than other benzodiazepines used in epilepsy (5). Its most common adverse effects are mild and transient drowsiness, dizziness, or fatigue rather less common are muscle weakness, restlessness, aggressiveness, weight increase, ataxia, mood disorders, psychotic and behavioral disturbances, vertigo, hypotonia, hypersalivation, and edema (SED-13, 152). There may be a loss of therapeutic response over time. 

Clobazam has similar effects on anxiety to other benzodiazepines, but may be better tolerated (SEDA-20, 31). Used as an anticonvulsant, clobazam is generally well tolerated in epileptic patients, many showing little evidence of tolerance (5). On the other hand, children with epilepsy appear unusually prone to adverse behavioral reactions when taking clobazam (SEDA-19, 34). 

Fig. 3. Separation of some benzodiazepines using System HI. A, clorazepic acid B, nitrazepam C, clobazam D, oxazepam E, temazepam F, chlordiazepoxide G, diazepam H,...

SYNS CHLOREPIN CLOBAZAM CLOREPIN FRISIUM H-4723 HR 376 LM-2717 l-PHENYL-5-METHYL-8-CHLORO-l,2,4,5-TETRAHYDRO-2,4-DIOXO-3H-1,5-BENZODIAZEPINE RU-4723 URBANYL... 

Die Spektren von chlordiazepoxide hydrochloride [2602] und von clobazam [2603] (1,5-Benzodiazepin-2,4-dion) sind von denjenigen der vorgenannten Reihe deutlich unterschieden. 

The best-known and most-used anxiolytics are the benzodiazepines, of which those in use include alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, diazepam, flunitrazepam, halazepam, loprazolam, lorazepam, medazepam, midazolam, oxazepam, quazepam, temazepam and triazolam. The benzodiazepines work by acting as benzodiazepine binding-SITE AGONISTS at a site of the GABA receptors. 

Archetypal benzodiazepines contain a 5-aryl substituent ring and a 1,4-diazepine ring, so the term benzodiazepine drug has come to refer to 5-aryl-1.4-benzodiazepine. Various modifications of the ring system have yielded compounds with similar activity. These include 1,5-benzodiazepines (e.g. clobazam) and replacement of the fused benzene ring with heteroaromatic systems such as thieno (e.g. brotizolam). 

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