Related Experiment Video
Updated: Feb 12, 2026
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition
Sean P Moran1,2,3, Jonathan W Dickerson2,3, Hyekyung P Cho2,3
1Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA.
Summary
New M1 positive allosteric modulators (PAMs) show promise for cognitive disorders. However, some M1 PAMs with intrinsic agonist activity may cause adverse effects and reduce efficacy, unlike those without agonist activity.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- Selective positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) are investigated for treating cognitive deficits in Alzheimer's disease and schizophrenia.
- Excessive M1 mAChR activation can lead to seizures and prefrontal cortex (PFC) dysfunction, potentially impairing cognitive function.
Purpose of the Study:
- To evaluate M1 PAMs for their intrinsic agonist activity and their effects on M1 receptor activation in vitro and in vivo.
- To determine if M1 PAMs lacking intrinsic agonist activity can improve cognitive function without adverse effects.
Main Methods:
- Pharmacological, electrophysiological, and behavioral studies were conducted in cell lines and mice.
- M1 PAMs PF-06764427, MK-7622, VU0453595, and VU0550164 were tested for agonist activity, M1 activation in the mouse PFC, induction of behavioral convulsions, and cognitive enhancement in a novel object recognition assay.
Main Results:
- PF-06764427 and MK-7622 exhibited robust agonist activity in cell lines and PFC, with MK-7622 inducing severe convulsions.
- VU0453595 and VU0550164 were devoid of intrinsic agonist activity and demonstrated activity-dependent M1 activation in the PFC.
- VU0453595 improved cognitive function without inducing convulsions, whereas MK-7622 failed to improve cognition and caused adverse effects.
Conclusions:
- M1 PAMs lacking intrinsic agonist activity can enhance cognitive function effectively and safely.
- Intrinsic agonist activity in M1 PAMs may be associated with adverse effects and diminished cognitive-enhancing efficacy.
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