# M1 PAMs for Age-Related Cognitive Impairments

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $736,423

## Abstract

PROJECT SUMMARY
It is estimated that in the United States alone there will be nearly 70 million people over the age of 65 by the
year 2030. Yet, there remains a critical unmet need to understand and identify novel therapeutic strategies to
address age-related impairments in arousal, cognitive function, and sleep architecture. Agents such as
acetylcholinesterase inhibitors (AChEIs) that enhance overall cholinergic transmission or activate muscarinic
acetylcholine receptors (mAChRs) have been developed to ameliorate the loss of cognitive function in normal
aging and Alzheimer’s disease (AD) populations. Accumulating evidence indicates that enhancement of central
cholinergic neurotransmission through activation of the M1 mAChR subtype represents an exciting alternative
approach for the treatment of impairments in cognition, arousal and sleep observed in normal aging and AD.
M1 is co-localized with the NR1a subunit of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR).
Selective activation of M1 potentiates prefrontal cortical (PFC) and hippocampal NMDAR currents and
enhances both PFC- and hippocampal-mediated associative learning and memory functions. Recently we
successfully optimized a novel series of isoindolinone M1 positive allosteric modulators (PAMs), represented by
VU0453595, as an alternative strategy for the selective activation of M1. The discovery and characterization of
VU0453595 represents an unprecedented opportunity to characterize the impact of selective M1 potentiation
on cortical ACh neurotransmission and cognition, arousal and sleep dysfunction associated with normal aging
in preclinical species. In Aim 1, we will determine effects of VU0453595 alone and in combination with the
AChEI donepezil on cortical acetylcholine and glutamate neurotransmission using in vivo microdialysis
techniques in young and aged male and female mice. Next, we will examine effects of VU0453595 alone and
in combination with donepezil to ameliorate age-related impairments in cognition and sleep architecture in
aged male and female mice (Aim 2). Finally, in Aim 3 we will investigate whether selective activation of M1 by
VU0453595 ameliorates age-related impairments in cognition and sleep architecture in male and female aged
NHPs. Together, these translational studies across species will extend our understanding of age-related
cognitive dysfunction, a critical risk factor for later onset dementia and AD, and the potential role of M1
modulation for restoration of age-related impairments in cognition and sleep architecture.

## Key facts

- **NIH application ID:** 10160750
- **Project number:** 5R01AG054622-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Carrie Kimberly Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $736,423
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160750

## Citation

> US National Institutes of Health, RePORTER application 10160750, M1 PAMs for Age-Related Cognitive Impairments (5R01AG054622-05). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10160750. Licensed CC0.

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