An Approach to Discovering Novel Muscarinic M1 Receptor Positive Allosteric Modulators with Potent Cognitive Improvement and Minimized Gastrointestinal Dysfunction
Open accessAbstract
Activation of muscarinic M 1 receptor (M 1 R) is a promising approach for improving cognitive impairment in Alzheimer's disease. However, an M 1 R-selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M 1 R knockout mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS)-induced ileum contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M 1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction. We assessed PAM parameters of various M 1 PAMs with ≥100-fold selectivity over other muscarinic receptor subtypes by using in vitro binding and functional analysis. Evaluation of these M 1 PAMs in the Magnus assay revealed a significant correlation between percentage of ileum contractions at 1 μ M and their α-value, a PAM parameter associated with the binding cooperativity between acetylcholine and M 1 PAM. M 1 PAMs with lower α-value showed lower impact on EFS-induced ileum contraction. Next, we characterized in vivo profiles of two M 1 PAMs: compound A (log α = 1.18) and compound B (log α = 3.30). Compound A, at 30 mg/kg, significantly improved scopolamine-induced cognitive deficits without prominent signs of diarrhea at up to 1000 mg/kg in mice. In contrast, compound B, at 10 mg/kg, showed both significant improvement of scopolamine-induced cognitive deficits and severe diarrhea. Thus, fine adjustment of the α-values could be a key to discovering M 1 PAMs yielding potent cognitive improvement with a lower risk of GI effects.
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BQCA and PF06764427 achieve subtype selectivity through allosteric effects but have significant agonistic activity that may lead to side effects like diarrhea.
“M1-mAChR positive allosteric modulators (M1-PAMs), such as BQCA (53) and PF06764427 (54), achieve subtype selectivity through allosteric effects but have significant agonistic activity that may lead to side effects like diarrhea.544,553”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [553]
The Results identify BQCA as a highly selective M1 positive allosteric modulator and report diarrhea in treated mice but not M1-receptor knockout mice. The Discussion links the diarrhea to gastrointestinal M1 activation. Our copy does not address PF06764427 or establish that significant intrinsic agonistic activity in either compound causes the side effect. (LLM, conf=0.85)
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Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138 · see citing works
- Authors
- Kurimoto, E., Matsuda, S., Shimizu, Y., Sako, Y., Mandai, T., Sugimoto, T., Sakamoto, H., & Kimura, H.
- Affiliations
- Takeda (Japan) (JP)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 364
- Issue
- 1
- Pages
- 28-37
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2761452256
- Cited by
- 29
- References
- 54
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 9 · 2018: 2
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- M1 muscarinic receptor, positive allosteric modulators, gastrointestinal dysfunction, diarrhea, ileum contraction, cooperative binding, scopolamine-induced cognitive deficits, Alzheimer's disease, cognitive enhancement, drug screening, muscarinic receptor selectivity
- MeSH terms
- Allosteric Regulation, Animals, Cognition Disorders, Cricetulus, Diarrhea, Dose-Response Relationship, Drug, Cricetinae, Humans, Ileum, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Organ Culture Techniques, Quinolines, Random Allocation, Structure-Activity Relationship, CHO Cells, Mice, Knockout, Nootropic Agents, Receptor, Muscarinic M1, Mice, Drug Discovery
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