Orexin Antagonists for Insomnia

Orexins (also called hypocretins) are neurotransmitters discovered in the 1990s - these chemicals play a part in the neurological mechanism that keep people awake.  Pharmaceutical companies are trying to exploit this discovery by developing drugs to interfere with the actions of orexins.

In the brain two receptors (chemical structures at the cellular level) respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R)  The drug companies are trying to build orexin antagonists to treat insomnia

Drugs that are antagonists bind to the receptors but do not activate them.  That means antagonists crowd out the actual biochemical substrates that normally activate them.  Orexin receptors are part of the circuit that keeps people awake.  Insertion of an antagonist to the circuit suppresses the arousal, and the body’s natural sleep promoters can win the battle.

In contrast to most prescription insomnia medicines that affect the GABA neurotransmitter system and increase sleepiness levels, orexin antagonists work on the arousal side of the equation.  Even in early tests in animals, scientists noted that rats given the new drugs moved around less. There were early concerns that orexin antagnoists might negatively affect learning and memory, but animal tests found this wasn’t the case.

A paper published by Polish scientists claims dual-action orexin antagonists "do not change the sleep architecture and have limited side-effects." We have to be a little skeptical of that claim until we see more evidence. But this is an intriguing field.


The drug company Merck successfully developed a compound called suvorexant (C23H23ClN6O2) for insomnia treatment.  Approved in 2014, it hit the market for prescription in 2015. Biochemically, it is an antagonist of OX(1)R and OX(2)R.

This drug is the first, and so far only, orexin antagonist to get through the regulatory approval process and hit the market.  A drug called almorexant was under investigation, but the drug companies (GlaxoSmithKline and Actelion) concluded it would not be approved and abandoned work on it. GlaxoSmithKline has another orexin agonist code-named SB-649868.  It is mentioned in recent scientific papers and was included on a list of drugs in development by GSK in 2011, so it seems to be in development.

The Swiss company Actelion seems to be active in this area, investigating a series of compounds "based on a N-glycine-sulfonamide core". The Japanese company Takeda (developer of Ramelteon) is working on compounds based on benzoxazepine. Merck is pursuing "substituted diazepan compounds" if this European patent application is any evidence.

Orexin Agonists

There is also interest in development of agonists for the orexin system. An agoist is the opposite of an antagonist, and an orexin agonist would keep people awake by increasing arousal levels. Right now wake-promoting drugs such as the amphetamines and methylphendate act on the dopamine system. Orexin agnoists would presumably work on a different biochemical pathway.

Such diseases as narcolepy cause excessive sleepiness and drug companies are always on the lookout for new, safe arousal agents. At this time, however, no orexin agonists are on the market.


Insomnia drugs like Ambien are notorious for their side effects. Has Merck created a blockbuster replacement? - News

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