GAT229

GAT229 is a positive allosteric modulator of cannabinoid receptor 1 (CB₁) and the S-(–) enantiomer of the CB₁ modulator GAT211.^1,2 It does not activate the receptor on its own but enhances the binding and activity of CB agonists. GAT229 (1 µM) enhances the binding of the CB₁ full agonist CP 55,940 to CHO cells expressing human recombinant CB₁ (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. GAT229 (1 μM) enhances depolarization-induced suppression of excitation but does not inhibit excitatory postsynaptic currents (EPSCs) in murine autaptic hippocampal neurons.² GAT229 (0.2%, topical) reduces intraocular pressure by 5.8 and 7.7 mm Hg after 6 and 12 hours, respectively, in a transgenic mouse model of ocular hypertension using nose, ear, eye mutation (nee) mice.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. Cairns, E.A., Szczesniak, A.-M., Straiker, A.J., et al. The in vivo effects of the CB₁-positive allosteric modulator GAT229 on intraocular pressure in ocular normotensive and hypertensive mice. J. Ocul. Pharmacol. Ther. 33(8), 582-590 (2017).

Cairns, E.A., Szczesniak, A.-M., Straiker, A.J., et al. The in vivo effects of the CB₁-positive allosteric modulator GAT229 on intraocular pressure in ocular normotensive and hypertensive mice. J. Ocul. Pharmacol. Ther. 33(8), 582-590 (2017).