BioWorld International Correspondent

LONDON - Blocking the receptors for two types of brain peptide called orexins may be a useful new strategy for the development of novel compounds to treat insomnia, new research suggested.

Studies have shown that blocking both receptors, called OX1 and OX2, causes sleepiness in rats, dogs and humans.

In animals, the amount of rapid eye movement sleep (REM sleep) was higher than normal, an effect never seen before with existing pharmacological treatments for insomnia.

Francois Jenck, head of CNS Pharmacology at Actelion Pharmaceuticals Ltd., of Allschwil, Switzerland, told BioWorld International that "The dual antagonist we used in our study is the first, to our knowledge, orally active, brain-penetrating orexin receptor antagonist capable of inducing transient, reversible blockade of both OX1 and OX2 receptors in the brain."

The orexins, orexin A and orexin B, are peptides produced in the hypothalamus of the brain. They are ligands for two G-protein-coupled receptors called OX1 and OX2.

When they first were reported in 1998, the orexins were thought to be involved in regulating appetite and food intake. Then genetic studies showed that animals lacking receptors for those peptides suffered from the sleep disorder narcolepsy.

Subsequent research showed that orexin levels in the brain and cerebrospinal fluid of animals and humans are highest during the day and lowest toward the end of the sleep period. The neurons that produce orexins release their peptide cargo in synchrony when someone is awakened, and do not fire while the animal or person is asleep.

Jenck and his colleagues decided to find out whether it was possible to induce sleep by blocking the OX1 and OX2 receptors. At Actelion, they took five years to develop an OX1/OX2 receptor antagonist called ACT-078573.

Preclinical tests on rats and dogs showed that ACT-078573 resulted in an increase in REM sleep. In comparison, giving GABA-A receptor modulators such as zolpidem to humans is known to result in a decrease in REM sleep. These latter drugs also have a range of unwanted side effects. REM sleep is the phase of sleep where dreams occur, and it is thought to play a key role in the consolidation of memory.

The researchers also carried out a Phase I study on 70 healthy male volunteers. When those men took a single dose of 200-mg ACT-078573, they began to show signs of sleep within one hour. When the dose was increased, up to 1,000 mg, there were no severe or serious adverse side effects. After a 400-mg dose, signs of sleep disappeared after six hours. The study was placebo controlled, and it compared the response with that following 10 mg of zolpidem, which is a GABA-A receptor modulator.

The results are reported in the Jan. 28 issue of Nature Medicine, in a paper titled "Promotion of sleep by targeting the orexin system in rats, dogs and humans."

Roland Haefeli, corporate spokesman for Actelion, told BioWorld International, "The results indicate that this is a drug that induces the classical signs of sleep in healthy male volunteers, in a setting where placebo had no effect, and zolpidem had its expected effect. While we have not yet been able to measure whether there is an increase in REM [in humans] we have already shown differences in sleep patterns and with electroencephalograms."

Haefeli said the company already has begun a Phase II study in patients with chronic insomnia. "We want to find out if this effect is true [in this group of patients], and if it is true, we want to know what dose is required to provide these patients with sleep, and what kind of sleep do we provide for them?" he said.

Existing drugs for insomnia, which modulate the GABA-A receptors, have a range of side effects, including memory loss, impairment of performance the following day and muscle weakness. While those side effects can be useful in various conditions, many people who would benefit from medication to help them sleep do not take the drugs available because of them, Haefeli said.

Fears that OX1/OX2 receptor antagonists might induce symptoms of narcolepsy have not been borne out by the study reported in Nature Medicine. The volunteers showed no sign of developing cataplexy, a sudden loss of muscle tone leading to collapse, often following emotional stimuli.

Jenck and his colleagues now plan to assess REM sleep in humans who are taking ACT-078573. If REM sleep is increased while taking the drug, they would like to know how that affects the subjects' memory the following day.