CB1R Allosteric modulator 4 is an effective and positive modulator of cannabinoid type-1 (CB1R), exhibiting significant biological activity. This compound inhibits the production of cAMP and demonstrates strong β-arrestin-2 recruitment [1].

CB1R, the most prevalent G-protein coupled receptor (GPCR) in the CNS, plays a vital role in various physiological processes, including neurotransmission and energy metabolism [1]. The CB1R Allosteric Modulator 4 (compound 66b) demonstrated significant pharmacological activity across different concentrations and durations. At concentrations ranging from 0.10 nM to 10μM for 30 minutes, the compound effectively inhibited forskolin-stimulated cAMP production in CHO hCB1R cells, with an EC50 value of 0.05 μM [1]. Furthermore, at the same concentration range but over a 90-minute period, it facilitated β-arrestin-2 recruitment in hCB1R-CHO-K1 cells, evidenced by an EC50 value of 0.163 μM [1]. Additionally, when applied at concentrations between 1.6 and 200 μM for 2 hours, the modulator not only maintained good biological activity but also exhibited enhanced aqueous solubility, reaching a solubility limit of 3.13 μM [1].