Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M₁ receptors.

ABSTRACT:

Background and purpose

We aimed to identify and develop novel, selective muscarinic M₁ receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease.

Experimental approach

We developed and utilized a novel M₁ 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 M₁ receptor selective molecules displaying desirable in v

SUBMITTER: Broad LM 

PROVIDER: S-EPMC6284335 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature