Sedatives, Hypnotics

Barbituric acid was first pre pared in 1864 by Adolf von Baeyer (page 112) A histori cal account of his work and the later development of barbiturates as sedative-hypnotics appeared in the October 1951 issue of the Journal of Chemical Education (pp 524-526)... 

Barbituric acid is the parent of a group of compounds known as barbiturates The bar biturates are classified as sedative-hypnotic agents meaning that they decrease the responsiveness of the central nervous system and promote sleep Thousands of deriva lives of the parent ring system of barbituric acid have been tested for sedative-hypnotic activity the most useful are the 5 5 disubstituted derivatives... 

Anxiolytics are compounds that act primarily to refleve the symptoms of anxiety although such agents can also be used as anticonvulsants, sedatives, hypnotics, and anesthetic agents (see Anesthetics). The principal class of anxiolytics, the BZs, shows dependence HabiUty (5) whereas newer agents such as buspkone [36505-84-7] and ritanserine [8705-43-2] produce antianxiety effects via central serotoninergic systems (6). 

Fig. 2. Structuies of phenothia2ines having sedative—hypnotic piopeities. See text.

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

The amino acids L-leucine, T-phenylalanine, L-tyrosine, and L-tryptophan all taste bitter, whereas their D-enantiomers taste sweet (5) (see Amino ACIDS). D-Penicillamine [52-67-5] a chelating agent used to remove heavy metals from the body, is a relatively nontoxic dmg effective in the treatment of rheumatoid arthritis, but T.-penicillamine [1113-41 -3] produces optic atrophy and subsequent blindness (6). T.-Penicillamine is roughly eight times more mutagenic than its enantiomer. Such enantioselective mutagenicity is likely due to differences in renal metaboHsm (7). (R)-ThaHdomide (3) is a sedative—hypnotic (3)-thaHdomide (4) is a teratogen (8). 

Insomnia is a related psychiatric illness having potentially serious consequences. In any given year up to one-third of the general population may experience insomnia and consequently considerable impact on quaUty of life. Potentially serious psychosocial, health, and socioeconomic consequences may foUow. Many sedative—hypnotics additionally have a firmly estabUshed position within the field of anesthesiology as premedication, inducing agents, and/or for maintenance in intensive care medicine. 

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. 

Glassification of Substance-Related Disorders. The DSM-IV classification system (1) divides substance-related disorders into two categories (/) substance use disorders, ie, abuse and dependence and (2) substance-induced disorders, intoxication, withdrawal, delirium, persisting dementia, persisting amnestic disorder, psychotic disorder, mood disorder, anxiety disorder, sexual dysfunction, and sleep disorder. The different classes of substances addressed herein are alcohol, amphetamines, caffeine, caimabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics, polysubstance, and others. On the basis of their significant socioeconomic impact, alcohol, nicotine, cocaine, and opioids have been selected for discussion herein. 

Other apphcations of sodium bromide iaclude use ia the photographic iadustry both to make light-sensitive silver bromide [7785-23-1] emulsions and to lower the solubiUty of silver bromides during the developing process use as a wood (qv) preservative in conjunction with hydrogen peroxide (14) as a cocatalyst along with cobalt acetate [917-69-1] for the partial oxidation of alkyl side chains on polystyrene polymers (15) and as a sedative, hypnotic, and anticonvulsant. The FDA has, however, indicated that sodium bromide is ineffective as an over-the-counter sleeping aid for which it has been utilized (16). 

Benzodiazepiaes have largely replaced barbiturates and barbiturate-like agents for use as anxiolytics and sedative—hypnotics. Because benzodiazepiaes rarely produce levels of CNS depression that require therapeutic iatervention, the need for analeptics has decreased considerably. 

The pseudo-barbiturate , 2-methyl-3-o-tolylquinazolin-4(3H)-one (methaqualone, Revonal 1017) has an even wider spectrum of activities than do the barbiturates proper it appears to be quite widely used as- a sedative, hypnotic, anticonvulsant, antispasmodic and local anaesthetic agent (63MI21301, b-75MI21301>. 

Chinoin-1045 (108) was including a series of structurally divers compounds designing sedative/hypnotic derivatives from novel substruc-tural graph-theoretical approach (98MI11). 

Since there was some evidence that these compounds owe their action to interference with the action of histamine, this class has earned the soubriquet "antihistamines." This class of drugs is further characterized by a spectrum of side effects which occur to a greater or lesser degree in various members. These include antispasmodic action, sedative action, analgesia, and antiemetic effects. The side effects of some of these agents are sufficiently pronounced so that the compounds are prescribed for that effect proper. Antihistamines, for example, are used as the sedative-hypnotic component in some over-the-counter sleeping pills. 

An analogous sequence on acid, 29 (obtained by decarboxylative hydrolysis of the malonic ester), leads to carbromal (30). Dehy-drohalogenation of 30 by means of silver oxide affords the corresponding olefin, ectylurea (31), itself a sedative-hypnotic. 

The continuing search for molecules that possess the sedative-hypnotic properties of the barbiturates but show a better pharmacologic ratio has, as shown above, taken many directions. To name only two variants, the ring has been contracted and even opened entirely in each case some activity of the parent was retained. Although at one time the acylurea functional array was thought necessary for activity, the work below shows that even... 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

The close structural resemblance between the sedative-hypnotic and anticonvulsant agents was mentioned earlier. It is interesting that the two activities can be related in at least one case by a simple chemical transformation. Thus, reductive desulfurization of the thiobarbituric acid, 158, affords primi-... 

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