GAT211

GAT211 is an agonist and positive allosteric modulator (PAM) of cannabinoid receptor 1 (CB₁) and a racemic mixture of GAT228 (Item No. 24485) and GAT229 (Item No. 24486), which have enantiomer-specific activities.¹ 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 (2-AG; Item No. 62160), arachidonoyl ethanolamide (AEA; Item No. 90050), 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.² 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.³

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1. Laprairie, R.B., Kulkarni, P.M., Deschamps, J.R., et al. Enantiospecific allosteric modulation of cannabinoid 1 receptor. ACS Chem Biol. 8(6), 1188-1203 (2017).

2. Mitjavila, J., Yin, D., Kulkarni, P.M., et al. Enantiomer-specific positive allosteric modulation of CB₁ signaling in autaptic hippocampal neurons. Pharmacol. Res. 129, 475-481 (2018).

3. Slivicki, R.A., Xu, Z., Kulkarni, P.M., et al. Positive allosteric modulation of CB₁ suppresses pathological pain without producing tolerance or dependence. Biol. Psychiatry 84(10), 722-733 (2018).