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Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M 1 receptors
Author(s) -
Broad Lisa M,
Sanger Helen E,
Mogg Adrian J,
Colvin Ellen M,
Zwart Ruud,
Evans David A,
Pasqui Francesca,
Sher Emanuele,
Wishart Graham N,
Barth Vanessa N,
Felder Christian C,
Goldsmith Paul J
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14510
Subject(s) - agonist , receptor , partial agonist , pharmacology , functional selectivity , drug discovery , neuroscience , in vivo , muscarinic acetylcholine receptor , chemistry , biology , biochemistry , microbiology and biotechnology
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.