PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems.

Moran SP, Cho HP, Maksymetz J, Remke DH, Hanson RM, Niswender CM, Lindsley CW, Rook JM, Conn PJ
ACS Chem Neurosci. 2018 9 (9): 2218-2224

PMID: 29683646 · PMCID: PMC6146053 · DOI:10.1021/acschemneuro.8b00106

Positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M PAMs may reduce efficacy and contribute to adverse effect liability. However, the M PAM PF-06827443 was reported to have only weak agonist activity at human M receptors but produced M-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.

MeSH Terms (15)

Allosteric Regulation Animals Calcium CHO Cells Cricetulus Dogs Humans Isoindoles Mice Oxazoles Patch-Clamp Techniques Prefrontal Cortex Rats Receptor, Muscarinic M1 Seizures

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