ArticleThe Journal of pharmacology and experimental therapeutics2008
Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats.
Article in The Journal of pharmacology and experimental therapeutics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed, 201 citations in OpenAlex.
- Molecular pharmacology of mGluMolecular pharmacology · 2026Article
- Novel drug treatments for schizophrenia.Nature reviews. Drug discovery · 2026Review
- Discovery of VU6025733 (AG06827): A Highly Selective, Orally Bioavailable, and Structurally Distinct MACS chemical neuroscience · 2026Article
- Beyond dopamine: KarXT and emerging mechanism-based therapies in schizophrenia.Frontiers in psychiatry · 2026Review
- The Novel Functions of M4 Muscarinic Receptors.Physiological research · 2025Review
- Overexpression of mGluMolecular neurobiology · 2025Article
- Discovery of Pre-Clinical CandidateACS chemical neuroscience · 2025Article
- Downstream Signaling of Muscarinic MPharmacology research & perspectives · 2025Article
- A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.Nature reviews. Drug discovery · 2024Review
- Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic MACS chemical neuroscience · 2024Article
- Activation of MBritish journal of pharmacology · 2024Article
- Co-stimulation of muscarinic M1 and M4 acetylcholine receptors prevents later cocaine reinforcement in male and female mice, but not place-conditioning.Progress in neuro-psychopharmacology & biological psychiatry · 2024Article
- Discovery of VU6008677: A Structurally Distinct Tricyclic MACS medicinal chemistry letters · 2024Article
- PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
- The cannabinoid CBJournal of receptor and signal transduction research · 2024Article
- A sex-specific effect of MFrontiers in molecular neuroscience · 2024Article
- Stimulation of the muscarinic receptor M4 regulates neural precursor cell proliferation and promotes adult hippocampal neurogenesis.Development (Cambridge, England) · 2024Article
- Development and Characterization of Novel Selective, Non-Basic Dopamine DMolecules (Basel, Switzerland) · 2023Article
- The muscarinic M4 acetylcholine receptor exacerbates symptoms of movement disorders.Biochemical Society transactions · 2023Review
- The Evolving Role of Animal Models in the Discovery and Development of Novel Treatments for Psychiatric Disorders.Advances in neurobiology · 2023Article
59 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Previous clinical and animal studies suggest that selective activators of M(1) and/or M(4) muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment of schizophrenia and Alzheimer's disease. However, highly selective centrally penetrant activators of either M(1) or M(4) have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. We previously identified VU10010 [3-amino-N-(4-chlorobenzyl)-4, 6-dimethylthieno[2,3-b]pyridine-2-carboxamide] as a potent and selective allosteric potentiator of M(4) mAChRs. However, unfavorable physiochemical properties prevented use of this compound for in vivo studies. We now report that chemical optimization of VU10010 has afforded two centrally penetrant analogs, VU0152099 [3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide] and VU0152100 [3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide], that are potent and selective positive allosteric modulators of M(4). VU0152099 and VU0152100 had no agonist activity but potentiated responses of M(4) to acetylcholine. Both compounds were devoid of activity at other mAChR subtypes or at a panel of other GPCRs. The improved physiochemical properties of VU0152099 and VU0152100 allowed in vivo dosing and evaluation of behavioral effects in rats. Interestingly, these selective allosteric potentiators of M(4) reverse amphetamine-induced hyperlocomotion in rats, a model that is sensitive to known antipsychotic agents and to nonselective mAChR agonists. This is consistent with the hypothesis that M(4) plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M(4) may mimic some of the antipsychotic-like effects of less selective mAChR agonists.
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