Therapeutic Targets
CB1 Positive Allosteric Modulators and Glaucoma
Glaucoma is a neurodegenerative disease and one of the leading causes of irreversible worldwide blindness. The reduction of intraocular pressure (IOP) strategy has been found to be most effective to reduce the risk of developing glaucoma and the progression of existing diseases. Several IOP-lowering eye-drops are available with a different mode of action and efficacy including β-blocker, carbonic anhydrase, prostaglandin analogs, α-2 adrenergic agonists, etc. Laser treatment and surgery have also been less commonly used for the treatment of glaucoma. However, the short duration of action, drug-penetration of existed eye drops, and practicability of laser and surgery treatment limited their uses for the effective treatment of glaucoma. From the last few decades ligands, targeting cannabinoid receptors have been evaluated for their IOP-lowering effect. Although CB1R orthosteric agonists can decrease IOP in humans and animals, their general therapeutic use is effectively precluded by a short duration of action (due to CB1R desensitization) and the possibility of psychotropic side effects. Alternatively, CB1R ago-PAM does not exhibit these adverse properties, suggesting that CB1R ago-PAMs administered alone or with a subthreshold concentration of CB1R orthosteric agonist may constitute a potentially safer and longer-lasting therapeutic approach for reducing IOP and obviating the risk of glaucoma-associated vision loss.
Our work with the CB1 PAM GAT229 demonstrated that the administration of CB1 PAMs may provide a novel approach to reduce IOP with fewer of the disadvantages associated with orthosteric CB1 activation. (https://doi.org/10.1089/jop.2017.0037)
We recently demonstrated that GAT1601, a “first-ever” biased allosteric modulator was devoid of undesirable side effects (triad test), and it reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (https://doi.org/10.1021/acs.jmedchem.1c00040)