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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 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 M1 receptors with activity conserved across species. SPP1 displays high functional selectivity for M1 receptors over native M2 and M3 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 M1 receptors. CONCLUSIONS AND IMPLICATIONS:We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M1 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 M1 receptors in physiology and disease.

SUBMITTER: Broad LM 

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

REPOSITORIES: biostudies-literature

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

Broad Lisa M LM   Sanger Helen E HE   Mogg Adrian J AJ   Colvin Ellen M EM   Zwart Ruud R   Evans David A DA   Pasqui Francesca F   Sher Emanuele E   Wishart Graham N GN   Barth Vanessa N VN   Felder Christian C CC   Goldsmith Paul J PJ  

British journal of pharmacology 20181116 1


<h4>Background and purpose</h4>We aimed to identify and develop novel, selective muscarinic M<sub>1</sub> receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease.<h4>Experimental approach</h4>We developed and utilized a novel M<sub>1</sub> 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  ...[more]

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