Other GABAa receptor modulators

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Gaboxadol (9) is a selective extrasynaptic GABA receptor agonist in late-stage investigation for the treatment of insomnia. The action of this compound was extensively reviewed in Chebib et al. [13] and updated in Wafford et al. [23]. Nevertheless, the sponsor companies Merck & Co., Inc., and H. Lundbeck A/S announced in March 2007 that the results from recently completed clinical studies do not support further development and announced the discontinuation of their joint development program for gaboxadol.

Tiagabine (10), a GABA reuptake inhibitor launched for epilepsy, is undergoing clinical trials for insomnia. Tiagabine 4, 6 and 8 mg significantly increased slow-wave sleep, with a significant decrease in Stage 1 sleep. Tiagabine was generally well tolerated, with doses of less than 6 mg having tolerability profiles similar to that of placebo. The 8-mg dose, however, was associated with troublesome adverse events [24].

A phase II study of EVT-201, a partial positive modulator of GABAA receptor, has recently been initiated in the US in elderly patients with chronic insomnia with the maintenance as primary endpoint (no structure disclosed).

NG2-73 is a GABAA receptor partial agonist that, according to the information given by the company, modulates preferentially the a3 subunit - a subunit that is hypothesized to be associated with sleep induction - and is undergoing phase II trials for chronic insomnia with primary endpoints measuring sleep onset as well as maintenance (no structure disclosed) [25].

Gaboxadol (9)

Tiagabine (10)

Gaboxadol (9)

Tiagabine (10)


Melatonin, secreted by the pineal gland, is produced at night to aid the body in regulating sleep-wake cycles. The amount of melatonin the body produces decreases with age, which may explain why the elderly suffer from insomnia more frequently than the general population. Melatonin may be helpful in treating patients with insomnia, however, its short half-life (minutes) limits its therapeutic use. A mela-tonin prolonged-release formulation (Circadin*) is currently undergoing a phase III study in the treatment of insomnia patients with low endogenous melatonin [26].

To mimic melatonin action and increase the half-life is the goal of melatonin receptor agonists, which are the more recent addition to the insomnia therapeutic armamentarium. These compounds, in addition to use for insomnia, may have potential application in the synchronization of disturbed circadian rhythms, sleep disturbances in the elderly, seasonal depression and jet lag, to name a few. Furthermore, studies have shown that melatonin receptor agonists do not induce any of the hypothermic, hypotensive or bradycardic effects caused by melatonin in humans [27,28].

Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed in Ann. Rep. Med. Chem., volume 39 [29]. Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research.

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The Insomnia Battle

The Insomnia Battle

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