Benzodiazepine Anxiolytic Agents

SEVEN-MEMBERED HETEROCYCLIC RINGS FUSED TO BENZENE 

of receptors that bind benzodiazepines. This receptor, which is actually part of a complex involved in gamma aminobutyric acid (GABA) regulation, has been subsequently shown to bind structurally unrelated agents active in the CNS such as, for example, zolpidem (see Chapter 15). 

The first starting material for building benzodiazepines was prepared inadvertently in a synthesis aimed at the benzodiazoxepine (6-1). The oxime acetamide (6-2) from 2-aminobenzophenone was thus treated with hydrogen chloride in the expectation that the new heterocycle would form by the elimination of water between the oxime and the enol form of the amide. The product mrned out in fact to be the quinazoline A-oxide (6-3), the product from the addition of the nucleophilic oxime nitrogen to the amide carbonyl group. 

One of the more important routes for the metabohsm of benzodiazepines involves the introduction of a hydroxyl group at the 3 position in the heterocychc ring. The fact 

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Quaglia, M. G., Farina, A., Bossu, E., and Dell aquila, C. (1995). Analysis of non-benzodiazepinic anxiolytic agents by capillary zone electrophoresis. /. Pharm. Biomed. Anal. 13, 505 — 509. 

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

The anxiolytic agent buspirone (131) is notable for the fact that it does not interact with the receptor for the benzodiazepines. This difference in biochemical pharmacology is reflected in the fact that buspirone (131) seems to be devoid of some of the characteristic benzodiazepine side effects. The spiran function is apparently not required for anxiolytic activity. Alkylation of 3,3-dimethylglutarimide with dichlorobutane in the presence of strong base yields the intermedi-... 

The development of the benzodiazepine class of drugs for the treatment of a variety of neurological indications has proven to be an outstanting success story in the field of chemotherapy. However, these compounds often produce undesirable side effects when used as anti-anxiety or hypnotic agents. These side effects include sedation, physical dependence, amnesia, muscle relaxation, and ethanol potentiation. The development of a benzodiazepine receptor-based anxiolytic agent devoid of these side effects would constitute a major advance in the field and has been the focus of significant research efforts [284]. 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Condensation of this with ethyl orthoacetate gives the anxiolytic agent brotizolam (167) [31]. 

Geriatric Considerations - Summary Benzodiazepines are effective anxiolytic agents, and hypnotics. These drugs should be reserved for short-term use. SSRls are preferred for long-term management of anxiety disorders in older adults, and sedat-... 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

The role of ChCMs as anxiolytic agents has not been extensively investigated. Clinical data have shown reduced anxiety in smokers and decreased anxiety induced by a stress-producing movie.77 With many patients suffering from anxiety, there is a concurrent overlap of depression, where two thirds of patients diagnosed with depression are anxious and almost all anxious patients will encounter an episode of depression.78 Benzodiazepines, such as diazepam, have long been the treatment of choice for anxiety. However, they are depressants and therefore could contribute to the depression in many patients, thereby limiting their use. 

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