The orexin receptor (also referred to as the hypocretin receptor) is a
G-protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...
that binds the neuropeptide
orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
. There are two variants,
OX1 and
OX2, each encoded by a different gene (, ).
Both orexin receptors exhibit a similar pharmacology – the 2 orexin peptides,
orexin-A
Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.
Structure
Orexin-A is a peptide composed of ...
and
orexin-B
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief losses ...
, bind to both
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...
and, in each case,
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
binding results in an increase in
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
calcium
Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
levels. However, orexin-B shows a 5- to 10-fold selectivity for orexin receptor type 2, whilst orexin-A is
equipotent
In mathematics, two set (mathematics), sets or class (mathematics), classes ''A'' and ''B'' are equinumerous if there exists a one-to-one correspondence (or bijection) between them, that is, if there exists a function (mathematics), function from ...
at both receptors.
Several
orexin receptor antagonists are in development for potential use in sleep disorders.
The first of these,
suvorexant, has been on the market in the United States since 2015. There were two orexin agonists under development :
oveporexton and TAK-360.
Ligands
Several drugs
acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as
narcolepsy
Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...
, or orexin antagonists for
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
. In August 2015, Nagahara et al. published their work in synthesizing the first HCRT/OX2R agonist, compound 26, with good potency and selectivity.
No
neuropeptide
Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
agonists are yet available, although synthetic orexin-A
polypeptide
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...
has been made available as a nasal spray and tested on monkeys. One non-peptide antagonist is currently available in the U.S.,
Merck's suvorexant (Belsomra),
two additional agents are in development:
SB-649,868 by GlaxoSmithKline
GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...
, for sleep disorders, and ACT-462206, currently in human clinical trials. Another drug in development,
almorexant (ACT-078573) by
Actelion
Actelion Pharmaceuticals Ltd. is a pharmaceuticals and biotechnology company established in December 1997, headquartered in Allschwil near Basel, Switzerland. The company is part of Johnson & Johnson Innovative Medicine business segment.
Actel ...
, was abandoned due to adverse effects.
Lemborexant, an orexin receptor antagonist, was approved for use in the United States in 2019.
Most
ligands
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...
acting on the orexin system so far are polypeptides modified from the endogenous agonists orexin-A and orexin-B, however there are some subtype-selective non-peptide antagonists available for research purposes.
Agonists
Non-selective
*
Orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
s – dual OX
1 and OX
2 receptor agonists
**
Orexin-A
Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.
Structure
Orexin-A is a peptide composed of ...
– approximately equipotent at the OX
1 and OX
2 receptors
**
Orexin-B
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief losses ...
– approximately 5- to 10-fold selectivity for the OX
2 receptor over the OX
1 receptor
*
AEX-5 – selective OX
1 receptor agonist; also a
cathepsin H inhibitor and
dopamine reuptake inhibitor
A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...
*
AEX-19 – dual OX
1 and OX
2 receptor agonist
*
AEX-24 – selective OX2 receptor agonist; also an "S1R" agonist
*
Mazindol – OX
2 receptor agonist
Selective
*
Alixorexton/
ALKS-2680 selective oral OX
2 receptor agonist
*
Danavorexton (TAK-925) – selective OX
2 receptor agonist
*
E-2086 – selective OX
2 receptor agonist
*
Firazorexton (TAK-994) – selective OX
2 receptor agonist
*
Oveporexton (TAK-861) – selective OX
2 receptor agonist
*
SB-668875 – selective OX
2 receptor agonist
*
Suntinorexton – selective OX
2 receptor agonist
* PhotOrexin –
photoswitchable orexin-B analogue to control the OX
2 receptor at nanomolar concentration ''in vivo''.
Antagonists
Non-selective
*
Almorexant (ACT-078573) – dual OX
1 and OX
2 receptor antagonist
*
Daridorexant (Quviviq; ACT-541468) – dual OX
1 and OX
2 receptor antagonist
*
Filorexant (MK-6096) – dual OX
1 and OX
2 receptor antagonist
*
GSK-649868 (SB-649868) – dual OX
1 and OX
2 receptor antagonist
*
Lemborexant (Dayvigo) – dual OX
1 and OX
2 receptor antagonist
*
Suvorexant (Belsomra) – dual OX
1 and OX
2 receptor antagonist
*
Vornorexant (ORN-0829, TS-142) – dual OX
1 and OX
2 receptor antagonist
Selective
*
ACT-335827 – selective OX
1 receptor antagonist
*
AZD-4041 – selective OX
1 receptor antagonist
*
C4X-3256 (INDV-2000) – selective OX
1 receptor antagonist
*
CVN-766 – selective OX
1 receptor antagonist
*
EMPA
The Swiss Federal Laboratories for Materials Science and Technology (Empa; :de:Eidgenössische Materialprüfungs- und Forschungsanstalt, German: ''Eidgenössische Materialprüfungs- und Forschungsanstalt'', :fr:Laboratoire fédéral d'essai des ...
– selective OX
2 receptor antagonist
*
JNJ-10397049 – selective OX
2 receptor antagonist
*
Nivasorexant (ACT-539313) – selective OX
1 receptor antagonist
*
Rocavorexant – selective OX
1 receptor antagonist
*
RTIOX-276 – selective OX
1 receptor antagonist
*
SB-334867 – selective OX
1 receptor antagonist
*
SB-408124 – selective OX
1 receptor antagonist
*
Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX
2 receptor antagonist
*
TCS-OX2-29 – selective OX
2 receptor antagonist
*
Tebideutorexant (JNJ-61393215; JNJ-3215) – selective OX
1 receptor antagonist
References
External links
*
*
{{Orexin receptor modulators
Protein families
G protein-coupled receptors