Cannabinoid receptor type 2 (CB2) is a G protein-coupled receptor of the cannabinoid receptor family. Specifically, the endogenous cannabinoid system consists of CB1 and CB2. Their endogenous ligands is relevant to enzymes for the synthesis, reuptake, and metabolism of endogenous cannabinoids. Besides, they have become an important neuroregulatory system for many brain functions. CB1 receptors are in the brain and, to some extent, in peripheral tissues. Moreover, the expression of CB2 receptor under normal physiological conditions is relevant to Ca2/3 pyramidal neurons in brain stem and hippocampus.

Furthermore, the changes in CB2R expression/function are closely related to various mental and neurological diseases. CB2 receptor can reduce the activation of microglia and improve the functional defects of neurodegenerative diseases. The effectiveness of CB2R agonists in animal models of stroke is affected by treatment. Meanwhile, CB2R plays an important role in the neuroinflammatory response. Nonetheless, CB2 is a neuromodulator and therapeutic target for neurodegenerative diseases including Parkinson’s disease (PD). Today, we will introduce a selective and orally available CB2 agonist, S-777469.

S-777469 is an Orally Active Cannabinoid Type 2 Receptor (CB2) Agonist.

To begin with, S-777469 is a selective and orally available CB2 agonist with a Ki of 36 nM. Importantly, S-777469 significantly suppresses compound 48/80-induced scratching behavior in mice in a dose-dependent manner. Particularly, S-777469 produces antipruritic effects by inhibiting itch signal transmission through CB2 agonist.

Secondly, S-777469 had moderate clearance and absorption across species. S-777469 had antipruritic effect. Obviously, S-777469 revealed significant inhibitions when dosed at 1, 3, 10 mg/kg (46%, 48%, 59%) of scratching induced by Compound 48/80.

Taken together, S-777469 significantly suppressed scratching behavior induced by histamine or substance P in mice or by serotonin in rats. Additionally, S-777469 significantly inhibited histamine-induced peripheral nerve firing in mice.

All in all, S-777469 is a selective and orally available CB2 agonist.


Haruna T, et al. Pharmacology. 2015;95(1-2):95-103.