Related Experiment Video
Updated: Feb 11, 2026

Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
Published on: October 4, 2024
PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve
Sean P Moran1,2,3, Hyekyung P Cho2,3, James Maksymetz2,3
1Vanderbilt Brain Institute , Vanderbilt University , Nashville , Tennessee 37232 , United States.
Abstract:
Positive allosteric modulators (PAMs) of the M1 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 M1 PAMs may reduce efficacy and contribute to adverse effect liability. However, the M1 PAM PF-06827443 was reported to have only weak agonist activity at human M1 receptors but produced M1-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M1 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.
Related Concept Videos
Cooperative Allosteric Transitions
Cooperative Allosteric Transitions
Cooperative Allosteric Transitions
Allosteric Regulation
Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...

