Benzodiazepines As Anxiolytic Agents

The treatment of anxiety and sleep disorders is dominated by the BZDs. These drugs induce sleep (act as hypnotics) in high doses and lead to sedation and reduced anxiety (anxiolytic) at lower doses. They function by an enhancement of the GABA-mediated inhibition of the CNS and act in an allosteric manner on the GABA receptor. The discovery of the

BZDs was both fortuitous in the nature and the timing of their discovery.

NHMe

4.73 4.74

A number of animal screens for tranquilizers involving relaxing muscle in the cat and foot shock tests on mice were available in the 1950s. Today such screening tests would be replaced by receptor and enzyme screens. In 1955, a series of quinazoline derivatives were being examined. Treatment of the quinazoline N-oxide 4.73 with methylamine gave an unknown compound, which was not tested until the project was coming to an end in May 1957. The compound showed activity comparable to the well-known tranquilizers phenobarbital and chlorproma-zine. Chemical studies then established the structure as a benzodiazepine 4.74. The patent was filed in May 1958 and granted in July 1959 and the compound was marketed in 1960 as chlordiazepoxide (Librium®). This rapid timescale is very different from that which occurs today and reflects the caution with which new medicines are now introduced.

Studies on related compounds showed that not all the structure was required and activity was found with diazepam (Valium®) 4.75. This led to many other BZDs including temazepam 4.76 and nitrazepam 4.77.

4.75 4.76 4.77

The synthesis of the BZDs, e.g., 4.75, from an aminobenzophenone 4.78 via the chloro- and amino-acetyl derivatives 4.79 and 4.80 and the cyclic amide 4.81, fulfils the criterion for a useful medicinal chemistry synthesis in terms of its flexibility. Many structural variations have been synthesized with different substituents on the aromatic rings and with different units attached to the seven-membered diazepine ring.

The BZDs function by binding in an allosteric manner to the GABAa receptor close to the GABA binding site. This binding alters the shape of the receptor so that the effect of GABA is changed. The consequence of this is an enhanced and in some instances longer opening of the ionchannel.

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