ArticleProceedings of the National Academy of Sciences of the United States of America2024
Targeting the muscarinic M1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It carries an expression of concern. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Selective inhibition of TLR2 stimulates the maturation of oligodendroglial progenitor cells to oligodendrocytes.NeuroImmune pharmacology and therapeutics · 2026Article
- Discovery of VU6077564: A Selective MACS chemical neuroscience · 2026Article
- From insights to innovations: evaluating preclinical paradigms in demyelinating disease therapeutics.Lab animal · 2026Review
- Quantification and Localisation of New Brain Lipid Synthesis Using Deuterium Oxide and High Resolution Mass Spectrometry.Angewandte Chemie (International ed. in English) · 2026Article
- SV2A PET reveals synaptic density loss in experimental autoimmune encephalomyelitis and in a pilot multiple sclerosis study.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Translational molecular imaging and drug development in multiple sclerosis.Theranostics · 2026Review
- Review
- Review
- New Horizons for Multiple Sclerosis Therapy: 2025 and Beyond.Annals of neurology · 2025Review
- Muscarinic Receptor Antagonism and TRPM3 Activation as Stimulators of Mitochondrial Function and Axonal Repair in Diabetic Sensorimotor Polyneuropathy.International journal of molecular sciences · 2025Review
- Repair mechanisms of the central nervous system: From axon sprouting to remyelination.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Myelin dysfunction in aging and brain disorders: mechanisms and therapeutic opportunities.Molecular neurodegeneration · 2025Review
- Clemastine enhances myelin formation in the striatum and medial prefrontal cortex and improves sociability in a neonatal rat hypoxic-ischemic model.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Review
- The potential of repurposing clemastine to promote remyelination.Frontiers in cellular neuroscience · 2025Review
- Demyelination and neurodegeneration early in experimental autoimmune encephalomyelitis contribute to functional deficits in the anterior visual pathway.Scientific reports · 2024Article
- Pipe dream: Remyelination therapy for multiple sclerosis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
Corrections and comments
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- Erratum issued
- Expression of concern
Authors and funding
13 authors.
Funding
Abstract
Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.
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