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6.06.6.4.2 Antihistamines (^-antagonists)

The early CNS-permeable H antagonists have long been known for their sedating side effects. Such compounds include diphenhydramine, 34, doxylamine, 35, chlorpheniramine, 36, and hydroxyzine, 37. Diphenhydramine or doxylamine are common components of over-the-counter antihistamines used for insomnia.

NMe2

34 Diphenydramine

NMe2

35 Doxylamine

36 Chlorpheniramine

NMe2

36 Chlorpheniramine

6.06.6.4.3 Classical benzodiazepines

Classical benzodiazepines (BZs) such as diazepam and triazolam have been mainstay hypnotic therapy for decades and target GABA, the major inhibitory neurotransmitter in the CNS. The classical BZs are allosteric modulators of the benzodiazepine site on GABAa receptors (see 6.04 Anxiety)19 and will not be discussed further in this chapter. Advances in sleep biology have also led to the development of other mechanistic approaches for the treatment of insomnia and new drugs are starting to appear. These agents (launched or in clinical evaluation) are described below and listed in Table 3.

6.06.6.4.4 GABAa benzodiazepine receptor (x1) antagonists

Despite their widespread use, the side effect profiles of classical BZs, which include altered sleep architecture, rebound insomnia, tolerance, respiratory depression, and abuse potential, have led to a search for more selective NCEs.76 A variety of novel selective, BZ receptor ligands that were not structurally BZs (the non-BZs) were identified, e.g., zolpidem, that had hypnotic efficacy similar to that of the traditional BZs with a reduced incidence of side effects have been identified (Table 3). These ligands specifically act at the o1 site on the GABAA receptor while classical BZs interact at both o1 and o2 sites, the latter site being implicated in their side effect profiles. The o1 GABAA receptor subtype is located in regions of the brain linked to sleep-wake regulation, mood, and cognition.

6.06.6.4.4.1 Zopiclone, Zolpidem, and eszopiclone

Zopiclone and Zolpidem (Table 3) were the first two non-BZs ('Z'-drugs based on their names) interacting at the ffl! binding site although this was not known when they advanced to the clinic. These drugs have the efficacy without the major liabilities of the classical BZs.77 Eszopiclone, the active S-( + )-isomer of racemic zopiclone was launched in the USA. It is approximately 50-fold more potent than the (— )-enantiomer in binding studies and is responsible for the hypnotic effects of the racemate. Eszopiclone is efficacious in insomnia and well tolerated.78 Eszopiclone produces euphoria to a similar to diazepam, in patients with histories of BZ abuse. No serious withdrawal symptoms were noted in clinical studies. Like the BZs these compounds are scheduled.

6.06.6.4.4.2 Zaleplon

Zaleplon is a pyrazolopyrimidine non-BZ hypnotic that has sedative, anxiolytic, muscle relaxant, and anticonvulsant activities.76 Zaleplon is equieffiacious to the BZs and Zolpidem. Zaleplon does not appear to cause significant morning memory impairment following night-time administration (which is sometimes observed with hypnotic therapy) nor rebound insomnia and it did not appear to cause withdrawal symptoms following discontinuation. The abuse liability is similar that that of other BZ hypnotics and the drug is classified schedule IV.

6.06.6.4.4.3 Indiplon

Indiplon is a triazolopyrimidine non-BZ that is a selective GABAA o1 agonist.79 In preclinical studies it was more potent than both zaleplon and zolpidem.74 In clinical trials, indiplon was well tolerated even in elderly patients, a major population among chronic insomniacs. Due to its short half-life (1-1.5 h) with no residual impairment, this NCE should be beneficial to insomniacs who find it difficult to resume sleep once awakened in the middle of the night.

6.06.6.4.5 Melatonin receptor agonists

6.06.6.4.5.1 Ramelteon

Melatonin and melatonin agonists are useful in the treatment of insomnia and other sleep-wake syndromes and ramelteon (TAK-375) is the first of a new class of hypnotics selectively interacting with the MT1 receptor (Table 3).

Table 3 Agents marketed/in development for the treatment of insomnia

Compound

Structure

Company

Development Mode of action phase

Zolpidem

Zopiclone

CONMe,

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Healthy Sleep

Healthy Sleep

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