Orexins A and B (
hypocretins 1 and 2) and their two receptors (OX1R and OX2R) were discovered in 1998 by two different groups.
Orexin A and B are derived from the differential processing of a common precursor, the prepro-
orexin peptide. The
neuropeptides are expressed in a few thousand cells located in the lateral hypothalamus (LH), but their projections and receptor distribution are widespread throughout the brain. Remarkably, prepro
peptide and double (OX1R/OX2R) receptor knock out (KO) mice reproduce a sleep phenotype known in humans and dogs as
narcolepsy/
cataplexy. In humans, this disease is characterized by the absence of
orexin producing cells in the LH, and severely depleted levels of
orexin the cerebrospinal fluid. Null mutation of the individual OX1R or OX2R in mice substantially ameliorates the
narcolepsy/
cataplexy phenotype compared to the OX1R/OX2R KO, and highlights specific roles of the individual receptors in sleep architecture, the OX1R KO demonstrating an a attenuated sleep phenotype relative to the OX2R KO. It has therefore been suggested that
orexin is a master regulator of the sleep-wake cycle, with high activity of the LH
orexin cells during wake and almost none during sleep. Less than 10years later, the first
orexin antagonist,
almorexant, a
dual orexin receptor antagonist (DORA), was reported to be effective in inducing sleep in volunteers and
insomnia patients. Although development was stopped for
almorexant and for Glaxo's DORA
SB-649868, no less than 4
orexin receptor antagonists have reached phase II for
insomnia, including
Filorexant (MK-6096) and
Suvorexant (MK-4305) from Merck.
Suvorexant has since progressed to Phase III and dossier submission to the FDA. These four compounds are reported as DORAs, however, they equilibrate very slowly at one and/or the other
orexin receptor, and thus at equilibrium may show more or less selectivity for OX1R or OX2R. The appropriate balance of antagonism of the two receptors for sleep is a point of debate, although in rodent models OX2R antagonism alone appears sufficient to induce sleep, whereas OX1R antagonism is largely devoid of this effect.
Orexin is involved in a number of other functions including reward and feeding, where OX1R (possibly OX2R) antagonists display anti-addictive properties in rodent models of alcohol, smoking, and
drug self-administration. However, despite early findings in feeding and appetite control,
orexin receptor antagonists have not produced the anticipated effects in models of increased food intake or
obesity in rodents, nor have they shown marked effects on weight in the existing clinical trials. The role of
orexin in a number of other domains such as
pain, mood, anxiety,
migraine and
neurodegenerative diseases is an active area of research. The progress of the
orexin field is thus extraordinary, and the community awaits the clinical testing of more receptor selective antagonists in sleep and other disorders, as well as that of
orexin agonists, with the latter expected to produce positive outcomes in
narcolepsy/
cataplexy and other conditions.