Sleep Disorders

Gaboxadol

Also known as THIP hydrochloride; Molecular formula C6H8N2O2

CAS Number 64603-91-4

Gaboxadol is a GABA-A receptor agonist currently in Phase III clinical trials for sleep disorders.

Early clinical studies suggest that patients who take Gaboxadol experience increased amounts of slow wave sleep – Stages 3 and 4, which is deep sleep. If it works as its developers hope, Gaboxadol could be an important tool in the arsenal of doctors who treat the tens of millions of people who suffer from a chronic lack of sleep. Current sleep medications target receptors in the brain that promote sleep, but which can also lead to abuse and addiction. In contrast, Gaboxadol targets different receptors in the brain, which also promote sleep, but that may not lead to abuse and addiction.

Gaboxado is not as far along in the drug development process as eszopiclone or indiplon, but late-stage trials have begun. If the drug is successfully approved, it will probably become available in 2007.

Merck, Inc, licenses gaboxadol, from Danish pharmaceutical company Lundbeck for sale in the United States.

Following the recognition of GABA as an inhibitory neurotransmitter, the discovery of high affinity GABA uptake, and the characterisation of GABA receptors great progress has been made in developing GABA pharmacology. Tiagabide, the first marketed GABA uptake inhibitor may be followed by new and more selective uptake inhibitors. Knowledge of the molecular pharmacology of GABA-A receptors, both synaptic and non-synaptic, may lead to improved anti-anxiety/anticonvulsant agents devoid of the sedative and dependence liabilities of earlier compounds and new hypnotics. Gaboxadol (THIP) is an example of a novel hypnotic that acts on GABA-A receptors by a non-benzodiazepine mechanism. Exploiting neurosteroid interactions with GABAergic mechanisms also holds much future promise.

From

Curr Opin Pharmacol. 2006 Feb;6(1):30-6. Epub 2005 Dec 20.

Gaboxadol--a new awakening in sleep.

Wafford KA, Ebert B.

Merck, Sharp & Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.

Drugs that enhance synaptic gamma-aminobutyric acid (GABA)ergic neurotransmission are widely utilized in the clinical setting. Barbiturates and benzodiazepine receptor agonists, for example, both potentiate an inhibitory chloride conductance through GABA-gated channels, and thereby achieve their sedative-hypnotic effects.

The primary locus of action of these agents, and indeed most neuroactive drugs, is the postsynaptic junction. By contrast, gaboxadol, a selective extrasynaptic GABA receptor agonist and late-stage investigational treatment for insomnia, acts on a unique delta-containing GABAA receptor subtype found exclusively outside of the synapse. Although the mechanistic details of extrasynaptic neurotransmission remain to be fully established, it is now clear that these receptors demonstrate unique pharmacological, biophysical and electrophysiological properties. Importantly, the delta-containing GABAA receptor subtype activated by gaboxadol is highly expressed in the thalamus, where it might behave as a 'gain control' (independently controlling the strength of signals) in the corticothalamic pathways that govern sleep-relevant neuronal oscillations.

This unique mechanism has contributed to our increased understanding of sleep mechanisms, and targeting of this system offers potential advantages over existing insomnia treatments.

Effect of repeated gaboxadol administration on night sleep and next-day performance in healthy elderly subjects.