Histamine receptors are a type of G protein-coupled receptor (GPCR), including four subtypes: H1, H2, H3, and H4 receptors. They have different functions. For example, the H1 receptor regulates circadian cycles and vasodilatation, while the H2 receptor stimulates gastric acid secretion. Among them, H3 receptors are mainly expressed in the nervous system. The receptors can couple to Gi G-protein, inhibiting cAMP formation. Also, they can interact with calcium channels, reducing action potential mediated influx of calcium and then reducing neurotransmitter release. Therefore, the H3 receptor is a promising target for the treatment of cognitive disorders such as Parkinson’s disease, drug addiction, or obsessive-compulsive disorder (OCD).

Irdabisant (CEP-26401) is a selective, orally active, and blood-brain barrier (BBB) penetrant H3 receptor antagonist/inverse agonist.

Irdabisant has a high affinity to human and rat H3 receptors with Kis of 2.0 nM and 7.2 nM, respectively. This agent exhibits relatively low inhibitory activity against hERG current with an IC<sub>50</sub> of 13.8 μM, and weakly inhibits CYP450 isoforms. It suggests that Irdabisant has fewer drug-drug interactions and is safe.

In addition, the H3 receptor antagonist shows good effects in animals. Firstly, Irdabisant (1 mg/kg for i.v. and 3 mg/kg for p.o.; single dosage) is rapidly absorbed with high oral bioavailability in rats and monkeys and shows a moderate clearance in monkeys and dogs compared to rats. Secondly, it (0.01-0.3 mg/kg; p.o.) dose-dependently inhibits H3R agonist RAMH-induced dipsogenia; and improves performance in the rat social recognition model of short-term memory as well. Thirdly, Irdabisant exhibits wake-promoting activity in rats and increases prepulse inhibition (PPI) in DBA/2NCrl mice. Thus, it has the potential to research schizophrenia or cognitive impairment.

Overall, Irdabisant is a selective and orally active H3 receptor antagonist/inverse agonist, possessing pharmacokinetic properties, brain permeability, and safety profile.

[1] Hudkins RL, et al. J Med Chem. 2011 Jul 14;54(13):4781-92.
[2] Raddatz R, et al. J Pharmacol Exp Ther. 2012 Jan;340(1):124-33.