[1] Both orexin receptors exhibit a similar pharmacology – the 2 orexin peptides, orexin-A and orexin-B, bind to both receptors and, in each case, agonist binding results in an increase in intracellular calcium levels.
In August 2015, Nagahara et al. published their work in synthesizing the first HCRT/OX2R agonist, compound 26, with good potency and selectivity.
[8] 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),[9] two additional agents are in development: SB-649,868 by GlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials.
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.