The in Vivo Effects of the CB₁-Positive Allosteric Modulator GAT229 on Intraocular Pressure in Ocular Normotensive and Hypertensive Mice

Purpose: Orthosteric cannabinoid receptor 1 (CB₁) activation leads to decreases in intraocular pressure (IOP). However, use of orthosteric CB₁ agonists chronically has several disadvantages, limiting their usefulness as clinically relevant drugs. Allosteric modulators interact with topographically distinct sites to orthosteric ligands and may be useful to circumvent some of these disadvantages. The purpose of this study was to investigate the effects of the novel CB₁-positive allosteric modulator (PAM) GAT229 on IOP. Methods: IOP was measured using rebound tonometry in anesthetized normotensive C57Bl/6 mice and in a genetic model of ocular hypertension [nose, eyes, ears (nee) mice] before drug administration, and at 1, 6, and 12 h thereafter. Results: In normotensive mice, topical administration of 5 μL GAT229 alone at either 0.2% or 2% did not reduce IOP. However, a subthreshold dose (0.25%) of the nonselective orthosteric CB₁ agonist WIN 55,212-2, when combined with 0.2% GAT229, significantly reduced IOP compared with vehicle at 6 and 12 h. Similarly, combination of subthreshold Δ⁹-tetrahydrocannabinol (a nonselective orthosteric CB₁ agonist; 1 mg/kg) with topical 0.2% GAT229 produced IOP lowering at 6 h. In nee mice, administration of topical 0.2% GAT229 or 10 mg/kg GAT229 alone was sufficient to lower IOP at 6 and 12 h, and 12 h, respectively. Conclusions: The CB₁ PAM GAT229 reduces IOP in ocular hypertensive mice and enhanced CB₁-mediated IOP reduction when combined with subthreshold CB₁ orthosteric ligands in normotensive mice. Administration of CB₁ PAMs may provide a novel approach to reduce IOP with fewer of the disadvantages associated with orthosteric CB₁ activation.