OX₁ Receptor Antagonist

SB-334867 (SB 334867A) is an excellent,selective and blood-brain barrier permeable orexin-1 (OX1) receptor antagonist, shows selectivity over OX2 (pK_b=7.4), 100-fold over 5-HT_2B, 5-HT_2C with pK_i values of 5.4 and 5.3, respectively. SB-334867 reduces ethanol consumption and inhibits the acquisition of morphine-induced sensitization to locomotor activity in vivo.

Almorexant (ACT 078573) is an orally active, potent and competitive dual orexin receptor antagonist, with K_d values of 1.3 nM (OX1) and 0.17 nM (OX2), respectively. Almorexant reversibly blocks signaling of orexin-A and orexin-B peptides. Almorexant totally blocked the intracellular Ca²⁺ signal pathway. Almorexant stimulates caspase-3 activity in AsPC-1 cells and induces apoptosis.

Almorexant (ACT 078573) hydrochloride is an orally active, potent and competitive dual orexin receptor antagonist, with K_d values of 1.3 nM (OX1) and 0.17 nM (OX2), respectively. Almorexant hydrochloride reversibly blocks signaling of orexin-A and orexin-B peptides. Almorexant hydrochloride totally blocked the intracellular Ca²⁺ signal pathway. Almorexant hydrochloride stimulates caspase-3 activity in AsPC-1 cells and induces apoptosis.

MK-1064 is a selective and orally active OX₂R antagonist (K_i: 0.5 nM, IC₅₀: 18 nM). MK-1064 promotes sleep in vivo. MK-1064 can be used in the research of insomnia.

SB-674042 is a potent and selective non-peptide orexin OX₁ receptor antagonist (K_d=5.03 nM), exhibits 100-fold selectivity for OX₁ over OX₂ receptors with IC₅₀ values of 3.76 nM and 531 nM, respectively.

SB-408124 is a non-peptide OX1 receptor antagonist with K_is of 57 nM and 27 nM in whole cell and membrane, respectively. SB-408124 exhibits 50-fold selectivity over OX2 receptor.

TCS 1102 is a potent, dual orexin receptor antagonist, with Ki values of 0.2 nM and 3 nM for OX2 and OX1 receptors, respectively. TCS 1102 demonstrates excellent blood-brain barrier penetrability and moderate bioavailability in rats.

SB-334867 free base (SB334867A free base) is an excellent, selective and blood–brain barrier permeable orexin-1 (OX1) receptor antagonist, shows selectivity over OX2 (pK_b=7.4), 100-fold over 5-HT_2B, 5-HT_2C with pK_i values of 5.4 and 5.3, respectively. SB-334867 reduces ethanol consumption and inhibits the acquisition of morphine-induced sensitization to locomotor activity in vivo.

GSK1059865 is a potent orexin 1 receptor antagonist.

Fazamorexant (YZJ-1139) is an orally active dual orexin receptor antagonist, with an IC₅₀ of 32 nM against OX1R and an IC₅₀ of 41 nM against OX2R. Fazamorexant prolongs total sleep time and improves sleep efficiency. Fazamorexant is applicable to related research on insomnia.

JNJ-54717793, as a brain penetrant, is an orally active, selective and high affinity orexin-1 receptor (OX1R) antagonist (plasma EC₅₀=85 ng/mL). The K_i values of JNJ-54717793 for hOX1R (human OX1R) and hOX2R are 16 nM and 700 nM, respectively. JNJ-54717793 is a potent compound of anxiety disorders.

ACT-462206 is an orally active and potent dual Orexin 1/Orexin 2 receptor antagonist with IC₅₀s of 60 nM (Orexin 1) and 11 nM (Orexin 2), respectively. ACT-462206 exhibits brain penetration properties, and can be used for insomnia, stress/anxiety-related disorders and addiction research.

CVN766 is an orally active inhibitor of orexin 1 receptor antagonist with blood-brain permeability with the IC₅₀ values of 8 nM and >10 μM for OX1R and OX2R, respectively. CVN766 can be used for study schizophrenia.

Nivasorexant (ACT-539313) is an orally active, blood-brain barrier penetrant, selective orexin OX1R inhibitor. Nivasorexant specifically blocks central OX1Rs without affecting OX2Rs, and exhibits competitive inhibitory activity against CYP2C8, CYP2C9, CYP2C19 and CYP3A4 (IC₅₀ values are 25 μM, 8.6 μM, 1.6 μM, 19 μM/44 μM, respectively). Nivasorexant significantly reduces binge-like eating behavior of highly palatable food in rat models and has long-acting properties. Nivasorexant shows no relevant off-target activity against over 130 selected proteins, exhibits favorable safety profiles, and can be used for studies related to binge eating disorder.

SB-408124 Hydrochloride is a selective non-peptide orexin receptor 1 (OX1) receptor antagonist with K_is of 57 nM and 27 nM in whole cell and membrane, respectively. SB-408124 Hydrochloride exhibits 50-fold selectivity over OX2 receptor.

ACT-335827 is a selective, orally active, brain-penetrant orexin type 1 receptor antagonist. ACT-33582 acts on OXR1 and OXR2 with IC₅₀ values of 6 nM and 417 nM, respectively. ACT-33582 can be used in studies related to neurological disorders.

Orexin receptor antagonist 4 is potent and selective orexin 2 receptor (OX2R) antagonist with an IC₅₀ of 4.27 nM. Orexin receptor antagonist 4 is 61-fold selective for the OX2R over the OX1R (IC₅₀ of 295 nM) (WO2018206959A1; example 1).

Orexin receptor antagonist 7 (Compound 34) is an antagonist of the orexin receptor (OX1R), with a K_i value of 4.05 nM. Orexin receptor antagonist 7 shows no detectable activity towards OX2R and has very low affinities for the three opioid receptors (μ, δ, κ) (K_i > 1,000 nM). Orexin receptor antagonist 7 can be used for research on opioid addiction.