Orexin antagonists

Orexin antagonists are a class of drugs that inhibit the action of the neurotransmitters known as orexins, which are involved in the regulation of sleep and wakefulness, among other physiological processes. These compounds have emerged as significant therapeutic agents, particularly in the treatment of sleep disorders such as insomnia.

Overview

Orexins, also known as hypocretins, are neuropeptides produced in the hypothalamus. They play a crucial role in the regulation of the sleep-wake cycle, appetite, and energy expenditure. Orexin neurons project to various parts of the brain, including areas involved in wakefulness, such as the lateral hypothalamus and the brainstem. The disruption of orexin signaling has been implicated in sleep disorders, most notably in narcolepsy, a condition characterized by excessive daytime sleepiness and sudden loss of muscle tone (cataplexy).

Mechanism of Action

Orexin antagonists work by blocking the action of orexins at their receptors, orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). By inhibiting these receptors, orexin antagonists decrease wakefulness and promote sleep. There are two main types of orexin antagonists: dual orexin receptor antagonists (DORAs), which block both OX1R and OX2R, and selective orexin receptor antagonists (SORAs), which selectively block either OX1R or OX2R.

Clinical Applications

The primary application of orexin antagonists is in the treatment of insomnia, a condition characterized by difficulty falling asleep, staying asleep, or non-restorative sleep. These drugs offer a novel approach to insomnia therapy by targeting the underlying mechanisms of wakefulness rather than inducing sedation, as many traditional sleep medications do.

Approved Drugs

Several orexin antagonists have been approved for medical use, including:

• Suvorexant (Belsomra): The first approved dual orexin receptor antagonist for the treatment of insomnia.
• Lemborexant (Dayvigo): Another DORA approved for the treatment of insomnia.
• Daridorexant: A newer DORA approved for managing insomnia in various countries.

Safety and Side Effects

Orexin antagonists are generally well-tolerated, but they can cause side effects such as headache, dizziness, and next-day drowsiness. Because they act on the sleep-wake cycle, there is a potential for them to affect alertness and motor coordination, which could impair the ability to drive or operate machinery.

Future Directions

Research is ongoing to explore the potential of orexin antagonists in treating other conditions beyond insomnia, such as anxiety disorders, depression, and substance abuse. The role of orexins in various physiological processes suggests that orexin antagonists could have broad therapeutic applications.