Deepening insights into cholinergic agents for intraocular pressure reduction: systems genetics, molecular modeling, and

Parasympathetic activation in the anterior eye segment regulates various physiological functions. This process, mediated by muscarinic acetylcholine receptors, also impacts intraocular pressure (IOP) through the trabecular meshwork. While FDA-approved M3 muscarinic receptor (M3R) agonists exist for IOP reduction, their systemic cholinergic adverse effects pose limitations in clinical use. Therefore, advancing our understanding of the cholinergic system in the anterior segment of the eye is crucial for developing additional IOP-reducing agents with improved safety profiles. Systems genetics analyses were utilized to explore correlations between IOP and the five major muscarinic receptor subtypes. Molecular docking and dynamics simulations were applied to human M3R homology model using a comprehensive set of human M3R ligands and 1,667 FDA-approved or investigational drugs. Lead compounds from the modeling studies were then tested for their IOP-lowering abilities in mice. Systems genetics analyses unveiled positive correlations in mRNA expressions among the five major muscarinic receptor subtypes, with a negative correlation observed only in M3R with IOP. Through modeling studies, rivastigmine and edrophonium emerged as the most optimally suited cholinergic drugs for reducing IOP via a potentially distinct mechanism from pilocarpine or physostigmine. Subsequent animal studies confirmed comparable IOP reductions among rivastigmine, edrophonium, and pilocarpine, with longer durations of action for rivastigmine and edrophonium. Mild cholinergic adverse effects were observed with pilocarpine and rivastigmine but absent with edrophonium. These findings advance ocular therapeutics, suggesting a more nuanced role of the parasympathetic system in the anterior eye segment for reducing IOP than previously thought.