Benzodiazepines discovery

Nonbenzodiazepine Benzodiazepine Receptor Ligands. The simultaneous discovery of the molecular target for the BZs, the GABA /BZ receptor complex, by two teams of workers (34,35) resulted ia the identification of a number of atypical or anxioselective anxiolytics that, whereas not having the BZ pharmacophore, interacted direcdy with the central BZ receptor. The anxioselective nature of such agents was considered to be... 

To speed the process of drug discovery, combinatorial chemistry> has been developed to prepare what are called combinatorial libraries, in which anywhere from a few dozen to several hundred thousand substances are prepared simultaneously. Among the early successes of combinatorial chemistry is the development of a benzodiazepine library, a class of aromatic compounds much used as antianxiety agents. 

The discovery of the benzodiazepine receptor was quickly followed by their subdivision as evidenced by (see also Chapter 11) ... 

Finally, the presence in human post-mortem brain tissue of the active metabolite of diazepam, desmethyldiazepam, raised some curiosity and frank alarm (Sangameswaran et al. 1986). At the time of its discovery in the brain it was thought that there was no enzyme system capable of producing such halogenated compounds and that its presence in the brain reflected dietary intake from an environment contaminated by overuse of its parent compound. However, its discovery in stored brain tissue which had been obtained before the synthesis of the benzodiazepines allayed these fears. It is now thought possible that some benzodiazepines, including desmethyldiazepam, occur naturally and that they are taken in as part of a normal diet (Table 19.5). 

That the benzodiazepine structure was a prerequisite for the characteristic tranquilizer profile and specific binding at the benzodiazepine receptor was a long-held belief. This has now been shown not to be the case by the discovery of a range of different compounds that bind to the benzodiazepine receptor [Figure 29-2). These include the 3-carbolines (e.g., abecarnil), the triazolo-pyridazines [e.g., GL 218,872), the imidazopyridines (e.g., zolpidem), the cyclopyrrol ones [e.g., suriclone), and the pyrazoloquinolines. 

The benzodiazepines are one of the most widely used (and abused) classes of drugs they are widely used in the treatment of epilepsy, insomnia, anxiety, movement disorders, and a variety of other neurological disorders. The discovery of the benzodiazepines is a good example of the importance of serendipity. 

The discovery of benzodiazepines is a story of serendipity and certainly one that is difficult to predictably reproduce as part of a drug discovery program. Regrettably (or fortuitously), this story of the benzodiazepines is not an isolated example. Valproic acid, an agent used to treat epilepsy, migraine, chronic pain, and bipolar affective disorder, was also discovered by accident. 

GABA is the most comprehensively studied inhibitory neurotransmitter, and there are many reviews of its biochemistry and pharmacology. The reason for this great interest is the discovery that the most popular drugs of the 1970-1980s, the benzodiazepine tranquilizers or anxiolytics, as well as the previously popular barbiturates, act on the GABAergic neuronal system. 

Some naturally occurring neurotransmitters may be similar to drugs we use. For example, it is well known that the brain makes its own morphine (i.e., beta endorphin), and its own marijuana (i.e., anandamide). The brain may even make its own antidepressants, it own anxiolytics, and its own hallucinogens. Drugs often mimic the brain s natural neurotransmitters. Often, drugs are discovered prior to the natural neurotransmitter. Thus, we knew about morphine before the discovery of beta-endorphin marijuana before the discovery of cannabinoid receptors and anandamide the benzodiazepines diazepam (Valium) and alprazolam (Xanax) before the discovery of benzodiazepine receptors and the antidepressants amitriptyline (Elavil) and fluoxetine (Prozac) before the discovery of the serotonin transporter site. This un-... 

Unexpected results lead to the discovery of pyrazolo[4,3-r/][2,3]benzodiazepine 87 preparation from l -(/V,Ar-diaroyl)-amino-4-phenyl-[l,2,3]triazol-5-yl-methyltriphenylphosphonium ylide 85. Ylide formation was followed by a Dimroth-type rearrangement to 86 and to product 87 <1995TL5637> (Scheme 17). 

Cyclative cleavage to five- and six-membered ring heterocycles is dominated by the synthesis of hydantoins and diketopiperazines, respectively. In the seven-membered ring case, it is the benzodiazepine nucleus that has attracted attention, due to its status as a privileged structure in drug discovery. In the precombinatorial days, Camps et al,33 reported a... 

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