Scientists spot mechanism behind promising new sleep drug

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Scientists spot mechanism behind promising new sleep drug

http://www.news-medical.net/?id=20868

An experimental drug called gaboxadol may soon help millions of

bleary-eyed insomniacs get to sleep, and a multi-center team of U.S.

scientists believes they've pinpointed just how the drug works.

Neuroscientist researchers from Weill Cornell Medical College in New

York City; the University of Pittsburgh; and the University of

California, Los Angeles, say gaboxadol acts in a whole different way

from sleep aids such as Ambien, or older benzodiazepine drugs such

as Valium.

What's more, gaboxadol's unique mechanism of action could keep it

from disrupting the delicate ratio of REM to non-REM sleep -- a

problem plaguing many commercially available sleep aids.

Gaboxadol is currently in Phase III clinical trials as a sleep drug

by Merck & Co, in partnership with the Danish company Lundbeck.

" Drugs like Ambien work on the alpha-1 subtype of receptors for the

neurotransmitter GABA -- that's akin to an 'on/off switch' for the

central nervous system. On the other hand, gaboxadol works on

another subtype, called alpha 4 -- it's more of a 'dimmer switch'

that might help regulate sleep in a less disruptive way, " explains

co-researcher Dr. Neil on, Professor of Pharmacology in

Anesthesiology at Weill Cornell Medical College.

He and Dr. Gregg Homanics, Associate Professor of Anesthesiology and

Pharmacology at the University of Pittsburgh, are co-senior authors

on the paper. Drs. Carolyn Houser, Igor Spiegelman and Olsen

of UCLA also contributed to this research.

The findings were published recently in the Proceedings of the

National Academy of Sciences.

Each night, millions of Americans struggle with sleeplessness.

According to the National Sleep Foundation (NSF), almost six of 10

Americans report having insomnia at least a few nights weekly. As

many as 25 percent of people say they have used medications to help

them sleep at least once in the past year.

Numerous drugs are available to help people sleep, but nearly all

come with undesirable side-effects, such as lingering daytime

grogginess.

The search for a drug that might faithfully mimic natural human

sleep has led to gaboxadol, which was originally developed in

Denmark in the 1970s as a possible anticonvulsant for use in people

with epilepsy.

At the time, researchers shelved the drug, noting that it was too

sedating.

It was not until the mid-1990s that Dr. Marike Lancel at the Max

Planck Institute for Psychiatry in Munich, Germany, revisited

gaboxadol as a possible hypnotic, or sleep aid.

" In trials, it does appear to help people get to sleep, although the

exact way in which it does so has remained unclear, " according to

Dr. on.

It appears that, like Ambien, gabodoxal works with GABA, a key

central nervous system neurotransmitter that helps inhibit neuronal

activity.

However, GABA acts through a variety of receptor subtypes. Ambien

affects the " alpha 1 " subunit receptor, through a process

called " synaptic inhibition. "

Gaboxadol does not appear to work in this way, however.

In their study, Dr. on joined up with researchers at U. Pitt

and UCLA to determine the drug's precise mechanism of action.

First, they turned to U. Pitt graduate student Dev Chandra, who

genetically engineered a " knockout " mouse that lacked another key

GABA subunit, called alpha 4.

" The alpha 4 subunit is expressed at high levels in the thalamus --

a key neurological 'sleep center' -- so we suspected it might play a

role, " Dr. on explains.

In their experiments, normal mice became sedated when exposed to

gaboxadol. However, mice that lacked the alpha 4 subunit remained

awake and unaffected by the drug.

" That tells us that the drug needs this subunit in order to work, "

Dr. on says.

It also suggests that, unlike Ambien, gaboxadol doesn't trigger

sleep by the blunt 'on/off' mechanism of synaptic inhibition.

" Synaptic inhibition via the alpha 1 subunit simply gets neurons to

stop firing, " Dr. on explains.

" On the other hand, compounds that affect the alpha 4 subunit act

like a 'dimmer switch' -- down-regulating neuronal activity in the

thalamus, " he says.

The thalamus is the last key regulator of activity in the cerebral

cortex, and is needed for sleep. According to previous work done by

Dr. Fan Jia and Dr. on with Dr. Goldstein at Weill

Cornell, gaboxadol selectively activates receptors in the thalamus

with the alpha 4 subunit, which, in turn, may cause specific neurons

in the thalamus to begin firing at a very slow, regular rhythm.

" It's this pattern of firing that helps send our brains into

restful, slow-wave sleep, " Dr. on explains.

This more subtle, gradual reduction in neuronal firing works outside

the synapse and is called tonic inhibition.

" We need more in-depth study to prove all this, but we think this is

how gaboxadol is working, " Dr. on says. " If so, it would be

the first case where a sleep aid has made use of an extra-synaptic

receptor like alpha 4. "

In fact, preliminary research suggests that this type of tonic

inhibition may occur naturally.

" In other words, this drug may simply be replicating what goes on in

healthy brains, " Dr. on says. That's important, he says,

because the ideal sleep drug would mimic natural sleep processes --

offering users quick, uninterrupted sleep; a good balance between

REM and non-REM sleep states; and a refreshed, non-drowsy feeling

upon awakening.

" So far, it appears that gaboxadol may satisfy all those criteria, "

Dr. on says.

This study received no private finding. The mouse model used in the

study was developed with funding from the U.S. National Institutes

of Health.

Other co-authors include Dr. Fan Jia of Weill Cornell Medical

College, New York City; J. Liang and A. Suryanarayanan of the

University of California, Los Angeles; and D.F. Werner of the

University of Pittsburgh.

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