Several drugs acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as
narcolepsy, or orexin antagonists for
insomnia. 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 agonists are yet available, although synthetic orexin-A
polypeptide 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, for sleep disorders, and ACT-462206, currently in human clinical trials. Another drug in development,
almorexant (ACT-078573) by
Actelion, was abandoned due to adverse effects.
Lemborexant, an orexin receptor antagonist, was approved for use in the United States in 2019. Most
ligands 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 •
Orexins – dual OX1 and OX2 receptor agonists •
Orexin-A – approximately equipotent at the OX1 and OX2 receptors •
AEX-19 – dual OX1 and OX2 receptor agonist •
AEX-24 – selective OX2 receptor agonist; also an "S1R" agonist
Selective •
Alixorexton (ALKS-2680) – selective oral OX2 receptor agonist •
Cleminorexton (ORX750) – selective OX2 receptor agonist •
Danavorexton (TAK-925) – selective OX2 receptor agonist •
E-2086 – selective OX2 receptor agonist •
Firazorexton (TAK-994) – selective OX2 receptor agonist •
Ledasorexton – selective OX2 receptor agonist • PhotOrexin –
photoswitchable orexin-B analogue to control the OX2 receptor at nanomolar concentration
in vivo.
Antagonists Non-selective •
Almorexant (ACT-078573) – dual OX1 and OX2 receptor antagonist •
Daridorexant (Quviviq; ACT-541468) – dual OX1 and OX2 receptor antagonist •
Filorexant (MK-6096) – dual OX1 and OX2 receptor antagonist •
GSK-649868 (SB-649868) – dual OX1 and OX2 receptor antagonist •
Lemborexant (Dayvigo) – dual OX1 and OX2 receptor antagonist •
Suvorexant (Belsomra) – dual OX1 and OX2 receptor antagonist •
Vornorexant (ORN-0829, TS-142) – dual OX1 and OX2 receptor antagonist
Selective •
ACT-335827 – selective OX1 receptor antagonist •
AZD-4041 – selective OX1 receptor antagonist •
C4X-3256 (INDV-2000) – selective OX1 receptor antagonist •
CVN-766 – selective OX1 receptor antagonist •
EMPA – selective OX2 receptor antagonist •
JNJ-10397049 – selective OX2 receptor antagonist •
Nivasorexant (ACT-539313) – selective OX1 receptor antagonist •
Rocavorexant – selective OX1 receptor antagonist •
RTIOX-276 – selective OX1 receptor antagonist •
SB-334867 – selective OX1 receptor antagonist •
SB-408124 – selective OX1 receptor antagonist •
Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX2 receptor antagonist •
TCS-OX2-29 – selective OX2 receptor antagonist •
Tebideutorexant (JNJ-61393215; JNJ-3215) – selective OX1 receptor antagonist ==See also==