A CB1 receptor agonist and PAM
GAT211 is an agonist and positive allosteric modulator (PAM) of cannabinoid receptor 1 (CB1) and a racemic mixture of GAT228 and GAT229 , which have enantiomer-specific activities. GAT211 increases β-arrestin recruitment and cAMP inhibition in HEK293A cells expressing GFP-tagged human CB1 (hCB1-GFP) in a concentration-dependent manner. It also enhances the binding of the CB1 full agonist CP 55,940 to CHO cells expressing hCB1, as well as the activity of 2-arachidonoyl glycerol , arachidonoyl ethanolamide , and CP 55,940 in arrestin2 recruitment assays and increases ERK1/2 and PLCβ3 phosphorylation in HEK293 cells expressing hCB1. It inhibits excitatory postsynaptic currents (EPSCs) in a subset of CB1-expressing murine autaptic hippocampal neurons when used at a concentration of 1 µM. GAT211 also decreases mechanical hypersensitivity in wild-type (EC50 = 9.75 mg/kg), but not CB1 knockout, mice in a model of inflammatory pain induced by complete Freund's adjuvant (CFA), and decreases mechanical and cold allodynia in a mouse model of paclitaxel-induced neuropathic pain when used at doses of 10 and 20 mg/kg per day.
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