The Science of Orexin
Orexin, or hypocretin, neuropeptides are powerful neurotransmitters in the brain that control wakefulness and sleep, as well as behavioral arousal, mood, and energy homeostasis.
We are developing innovative medicines that harness the power of the orexin system to restore function in a broad range of neurological disorders.
The orexin peptides A and B are produced by an estimated 70,000 neurons located in a small region of the brain called the lateral hypothalamus (LH). These neurons project to many different brain areas and modulate other neurotransmitter systems including dopamine, histamine, serotonin, acetylcholine, and norepinephrine.
Orexin-A and Orexin-B are produced by alternative splicing of a single prepro-orexin peptide.
Orexin peptides signal through two G-protein coupled receptors, the Orexin Receptor 1 (OX1R) and 2 (OX2R), which are differentially expressed in the brain.
OX2R activation leads to arousal and promotes wakefulness, while the OX1R modulates the reward centers of the brain and is implicated in feeding and addictive behaviors.
The two orexin receptors have a markedly different and complementary distribution in the brain, suggesting they have distinct physiological roles acting through different neuronal pathways.
Physiological functions of orexin
Orexin neurons maintain wakefulness through activation of the OX2R, exciting various wake-promoting neurons in the basal forebrain, tuberomammillary nucleus, and other brain regions. OX2R activation also suppresses the temporary muscle paralysis that naturally occurs during REM sleep.
Orexin levels are higher during the day and activate OX2Rs to promote wakefulness, while orexin levels decrease at night to allow sleep. This repeating pattern of changes in orexin levels in the brain is called diurnal variation. Orexin neurons are effective integrators of multiple input signals such as circadian rhythm, motivation, rest, and visceral cues to regulate the balance between wake and sleep.
Therapeutic opportunity for orexin agonists
Narcolepsy Type 1 (NT1) is a rare neurological condition that affects the brain’s ability to regulate the normal sleep-wake cycle. It is caused by a profound and selective loss of the neurons in the LH that produce orexin.
We are designing novel small molecule orexin receptor agonists, and peptides based on natural orexin, to directly address the underlying disease pathology of NT1 and restore orexin neurotransmission in the brain.
In addition, we are following the growing understanding of orexin physiology to identify additional neurological disorders with unmet need that could be treated with orexin agonists as well as positive modulators, which would enhance the activity of natural orexin in the brain.
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