Benzodiazepine antianxiety agents

L B. The young man s anxiety is probably caused by the stress induced by a full college curriculum along with working 25 hours per week. A benzodiazepine antianxiety agent would help relieve his symptoms. 

Sedatives (also called hypnotics, sedative-hypnotics, minor tranquilizers, antianxiety agents) Secobarbital (barbiturate) Glutethimide (nonbarbiturate hypnotic) Diazepam (benzodiazepine antianxiety agent) Chloral hydrate (miscellaneous hypnotic) alcohol ( substance )... 

Roche converted 2-amino-5-chlorobenzophenone (147) into the first benzodiazepine antianxiety agent, chlorodiazepoxide (148) (Scheme 30). The ring enlargement was unexpected, and was soon incorporated into similar products. The same intermediate, 147, is the starting point for diazepam (149), and provides one of two routes to oxazepam (150) discovered at Wyeth (Scheme 31)82. The full range of benzodiazepines exceeds fifteen different drugs used as tranquillizers, and in some case as hypnotics. 

Benzodiazepines as antianxiety agents, 1, 170 as anticonvulsants, 1, 166 organometallic complexes, 7, 604 as sedatives, 1, 166 IH- 1,2-Benzodiazepines conversion to 3H-1,2-benzodiazepines, 7, 604 synthesis, 7, 597, 598, 604 3H-1,2-Benzodiazepines acid-catalyzed reactions, 7, 601 nucleophilic reactions, 7, 604 oxidation, 7, 603 synthesis, 7, 596 thermal reactions, 7, 600 5H-1,2-Benzodiazepines photochemical reactions, 7, 599 synthesis, 7, 603... 

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. 

Pharmacodynamic tolerance to the psychomotor effects of benzodiazepines has been demonstrated after single or multiple doses (File 1985 Greenblatt and Shader 1978 Rosenberg and Chiu 1985). Pharmacodynamic tolerance to the anxiolytic effect (over a 6-month period) has not been demonstrated (Rickels et al. 1983), and clinical experience supports the view that many patients with anxiety disorders require long-term therapy with benzodiazepines or alternative antianxiety agents. An important clinical consequence of tolerance to sedative effects is observed in benzodiazepine overdoses, when patients may initially be... 

Chlordiazepoxide is the pioneer member of the 1,4-benzodiazepines to be employed clinically as an antianxiety agent in humans. A number of methods based on extraction processes are available for the assay of this drug, namely spectrofluorometry, polarography and electron-capture GC-technique but RIA measures it directly in the blood without involving extraction and possesses very low sensitivity. 

Conversion of an amide a thioamide enhances the reactivity of that function since it favors the enol form and provides a better leaving group for addition-elimination reactions (mercaptide vs. hydroxide). Thioamides obtained by treatment of diazepi-none such as (15-1) or (16-1) with phosphorus pentasulhde provide starting materials for further modihcation of the benzodiazepine nucleus. (More recently developed reagents such as Lawesson s Reagent or hw(tricyclohexyltin) sulhde provide more convenient methods for that transformation.) Thus, reaction of the thioamide (15-2) with (9-allylhydroxylamine leads directly to the amidine, probably via an addition-elimination sequence of the thioenol tautomer of (15-2). There is thus obtained the antianxiety agent uldazapam (15-3) [17]. 

Benzodiazepines are a potent class of antianxiety agents. Compared with many other types of depressants, benzodiazepines are relatively safe and rarely produce... 

Many patients with anxiety also have symptoms of depression.47 It therefore seems reasonable to include antidepressant drugs as part of the pharmacological regimen in these patients. Hence, patients with a combination of anxiety and depression often take a traditional antianxiety agent such as a benzodiazepine along with an antidepressant.44 The pharmacology of the antidepressants is addressed in Chapter 7. 

The benzodiazepine derivatives class of antianxiety agents shares the property of binding to a benzodiazepine receptor, part of the GABA receptor-chloride channel complex whose function it modulates allosterically. Not only the anxiolytic effects of the benzodiazepines, but also the anticonvulsant, sedative, or muscle relaxant effects seem to be mediated by the GABA-related mechanism. Besides the direct involvement of the GABA system, in parallel or more downstream to this, several other neurotransmitters such as serotonin have been suggested to participate in different aspects of benzodiazepine action. 

The introduction of chlordiazepoxide (Librium) into clinical medicine in 1961 ushered in the era of benzodiazepines. Most of the benzodiazepines that have reached the marketplace were selected for their effectiveness as antianxiety agents, not for their ability to depress CNS function. However, all benzodiazepines possess sedative-hypnotic properties to varying degrees these properties are extensively exploited clinically, especially to facilitate sleep and ease anxiety. Mainly because of their remarkably low capacity to lead to fatal suppression of key CNS functions, the benzodiazepines have displaced barbiturates as sedative-hypnotic agents. 

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