Barbiturates discovery

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

If sedatives, barbiturates, antipsychotic drugs, stimulants, opiates and thyroid medications all outperform inert placebos in the treatment of depression, does this mean that any active drug can function as an antidepressant Apparently not. In September 1998 the pharmaceutical company Merck announced the discovery of a novel antidepressant with a completely different mode of action than other medications for depression. This new drug, which they later marketed under the trade name Emend for the prevention of nausea and vomiting due to chemotherapy, seemed to show considerable promise as an antidepressant in... 

It is interesting to note that one of the founders of modern psychiatry, Kraepelin, listed only nine substances that were available for the treatment of psychiatric illness in the 1890s. These were opium, morphine, scopolamine, hashish, chloral hydrate, a barbiturate, alcohol, chloroform and various bromides. Later Bleuler, another founder of modern psychiatry, added paraldehyde and sodium barbitone to the list. Thus psychopharmacology is a very recent area of medicine which largely arose from the chance discovery of chlorpromazine by Delay and Deniker in France in 1952, and of imipramine by Kuhn in Switzerland in 1957. 

The discovery of the sedative/hynoptic activity of derivatives of barbituric acid has led to very extensive dissections of that molecule. One outcome of this work is the realization that acylurea and acylamide derivatives often exhibit CNS depressant activity. A fair number of such molecules have been prepared that contain a succinimide or glutarimide pharmacophore. For example, Michael addition of cyanide to the stereochemically xmdefined cinnamate... 

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. 

The utility of barbituric acid derivatives as sedative-hypnotic agents is discussed in more detail later in this chapter. Studies on the chemical simplification of these pyrimidinetrione derivatives led to the discovery that pyridinediones, or glutarimides,... 

Barbiturates are compounds derived from barbituric acid, a substance discovered in 1863 by German chemist Adolf von Baeyer. The year after von Baeyer s discovery, German scientists von Mering and Fischer synthesized the first barbiturate. Production began on the drug called barbital, and medical practices began using it in treatment in 1882. 

Bromide (1857) was the first drug to be used for the treatment of epilepsy, but it is now obsolete. Phenobarbital, introduced in 1912, controlled patients resistant to bromides. The next success was the discovery in 1938 of phenytoin (a hydantoin) which is structurally related to the barbiturates. Since then many other drugs have been discovered, but phenytoin still remains a drug of choice in the treatment of major epilepsy. Over the past ten years there has been a dramatic increase in the number of new anticonvulsant drugs (vigabatrin, gabapentin, lamotrigine, topiramate, oxcarbazepine, levetiracetam), but none has been shown to be superior to the major standard anticonvulsants (phenytoin, carbamazepine and sodium valproate). 

Barbituric acid was first synthesized in 1864 by Adolph von Baeyer. It apparently was named at a tavern on St. Barbara s day and is derived from urea. At the turn of the century the great chemist Emil Fischer synthesized the first hypnotic (sleep-inducing) barbiturate, the 5,5-diethyl derivative, at the direction of von Mering. Von Mering, who made the seminal discovery that removal of the pancreas causes diabetes, named the new derivative of barbituric acid Veronal because he regarded Verona as the most restful city on earth. 

The developments of the 20th century defy detailing here. Suffice it to say that in this century came the discoveries of barbiturates, of hormones (and their chemical synthesis), of antibacterials and antibiotics, of oral diuretics, of better analgesics, and of a host of other compounds. Finally, the physician was provided with medications not only for the treatment of symptoms but often for the underlying cause of disease itself. 

Variability in patterns of drug metabolism has been recognized for some time, even before the discovery of P450s. For instance, the phenomenon of pharmacogenetic variation had been identified by the 1950s and the early work of Remmer showed the influence of barbiturates upon drug metabolism. Further, a number of congenital defects in steroid metabolism were known and some could be attributed to alterations in specific hydroxylations. Much of the subsequent work on inducibility has been done in experimental animal models and later, cell culture. 

Major events preceding this work are the fortuitous discovery of phenobarbital as an anticonvulsant agent, stmcture/hypnotic activity studies with barbiturates and hydantoins in the early 1920s by A.W. Dox in the Parke Davis laboratories, and the development of anticonvulsi-vant assay techniques in animals, by a number of laboratories. Phenytoin was the first item on the list of compounds sent to Putnam by Dox and W.G. Bywater in April 1936. It was found to have anticonvulsivants properties in animals late in 1936, but no public reports were issued until the following year. Clinical efficacy was established in 1937, but again no public reports were issued until 1938. Dilantin sodium capsules were prepared by Parke, Davis Co. and were ready for marketing the same year. ... 

The drug discovery process and an understanding of structure-aotivity relationships has taken us from very toxio medications that were dangerous at high doses and caused physical dependence (i.e., barbiturates) to medioations that are safe and apparently free from any abuse liability (i.e., ramelteon). These newer medioations, brought to us by basio soience techniques, will improve the quality of life for many who suffer from insomnia. 

One of the celebrated illustrations of serendipity in drug discovery has to be the cis-platin drugs. Turning off the current did not kill the interesting therapeutic effect on tumor cells, and some alert scientists found the reason why. Penicillin, barbiturates, and more recently Viagra definitely underline the case for serendipity as a metric in drug discovery. 

Since its discovery by Baeyer violuric acid (II) has been of perennial interest to chemists, largely on account of the beautifully colored salts which it forms. Baeyer prepared this substance by the action of nitrous acid on barbituric add (I), while Ceresole showed that it could be produced by the action of hydroxylamine hydrochloride on alloxan (HI). 

An important advance in the synthesis of riboflavin was made by Tishler and associates, by the discovery that iV-(i -D-ribityl)-2-arylazo-4,5-dimeth-ylaniline (but not the -6-arylazo isomer) would react directly with barbituric acid in a weak acid medium. Large amounts of unusually pure riboflavin can be synthesized by this procedure. 

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