1. Inositol Phosphate Accumulation in Vivo Provides a Measure of Muscarinic M1 Receptor Activation
- Author
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Susan M. Lotarski, Sarah Grimwood, Michael Popiolek, Veronica Reinhart, Jeremy R. Edgerton, Jennifer E. Davoren, Stefanus J. Steyn, John F. Harms, and David P. Nguyen
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0301 basic medicine ,chemistry.chemical_classification ,Muscarinic acetylcholine receptor M3 ,Muscarinic acetylcholine receptor M2 ,Muscarinic acetylcholine receptor M1 ,Pharmacology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Muscarinic acetylcholine receptor ,Muscarinic acetylcholine receptor M5 ,Muscarinic acetylcholine receptor M4 ,Inositol ,Inositol phosphate ,030217 neurology & neurosurgery - Abstract
The rationale for using M1 selective muscarinic acetylcholine receptor activators for the treatment of cognitive impairment associated with psychiatric and neurodegenerative disease is well-established in the literature. Here, we investigate measurement of inositol phosphate accumulation, an end point immediately downstream of the M1 muscarinic acetylcholine receptor signaling cascade, as an in vivo biochemical readout for M1 muscarinic acetylcholine receptor activation. Five brain penetrant M1-subtype selective activators from three structurally distinct chemical series were pharmacologically profiled for functional activity in vitro using recombinant cell calcium mobilization and inositol phosphate assays, and a native tissue hippocampal slice electrophysiology assay, to show that all five compounds presented a positive allosteric modulator agonist profile, within a narrow range of potencies. In vivo characterization using an amphetamine-stimulated locomotor activity behavioral assay and the inositol ph...
- Published
- 2016
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