Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M 1 receptors.

Background and Purpose: We aimed to identify and develop novel, selective muscarinic M ₁ receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease.
Experimental Approach: We developed and utilized a novel M ₁ receptor occupancy assay to drive a structure activity relationship in a relevant brain region while simultaneously tracking drug levels in plasma and brain to optimize for central penetration. Functional activity was tracked in relevant native in vitro assays allowing translational (rat-human) benchmarking of structure-activity relationship molecules to clinical comparators.
Key Results: Using this paradigm, we identified a series of M ₁ receptor selective molecules displaying desirable in vitro and in vivo properties and optimized key features, such as central penetration while maintaining selectivity and a partial agonist profile. From these compounds, we selected spiropiperidine 1 (SPP1). In vitro, SPP1 is a potent, partial agonist of cortical and hippocampal M ₁ receptors with activity conserved across species. SPP1 displays high functional selectivity for M ₁ receptors over native M ₂ and M ₃ receptor anti-targets and over a panel of other targets. Assessment of central target engagement by receptor occupancy reveals SPP1 significantly and dose-dependently occupies rodent cortical M ₁ receptors.
Conclusions and Implications: We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M ₁ receptors, identified by a novel receptor occupancy assay. SPP1 is amenable to in vitro and in vivo study and provides a valuable research tool to further probe the role of M ₁ receptors in physiology and disease.
(© 2018 The British Pharmacological Society.)