Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure

Abstract

Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ9-THC lowers intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ9-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors. However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL), an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG), substantially lowers IOP. Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye. Recently we have reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is commonly observed with Δ9-THC and other lipophilic cannabinoids. This approach allowed us to develop novel cannabinoids with a predictable duration of action and is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects. We have tested a novel class of compounds using a combination of electrophysiology in autaptic hippocampal neurons, a well-characterized model of endogenous cannabinoid signaling, and measurements of IOP in a mouse model. We now report that AM7410 is a reasonably potent and efficacious agonist at CB1 in neurons and that it substantially (30%) lowers IOP for as long as 5 h after a single topical treatment. This effect is absent in CB1 knockout mice. Our results indicate that the direct targeting of CB1 receptors with controlled-deactivation ligands is a viable approach to lower IOP in a murine model and merits further study in other model systems.

Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure

“…For instance, we have shown that it is possible to enhance endogenous cannabinoid signaling by blocking the cannabinoid-metabolizing enzyme monoacylglycerol lipase 37 and so lower ocular pressure. Similarly, we have found that activating CB1 directly 38 can achieve the same outcome. Our findings for THC suggest that a dual CB1/GPR18 agonist may prove advantageous.…”

The Effect of Inhaled Cannabis on Intraocular Pressure in Healthy Adult Subjects

“…28,29 In addition, non-psychotropic cannabinoids and other CB1 receptor targets are being investigated for potential treatments that avoid systemic effects. 30,31 There are several limitations to this study. First, the number of subjects in the placebo group was small and may have introduced error into the results from the natural variability in IOP during the diurnal period.…”

The Relationship Between Plasma Tetrahydrocannabinol Levels and Intraocular Pressure in Healthy Adult Subjects

“…However, novel compounds with improved corneal penetration are being developed for topical administration, thereby mitigating systemic side-effects (10)(11)(12)(13)(14)34). Non-psychotropic cannabinoids and other CB1 receptor targets are being investigated for potential treatments that avoid systemic effects (35,36). In addition, formulations are being developed to improve duration of action (37).…”