mAChR4
mAChR4/M4 muscarinic acetylcholine receptor is a GPCR that couples mainly to Gαi/o, inhibits adenylate cyclase, and lowers intracellular cAMP signaling[1]. In striatal neurons, M4 signaling restrains dopamine D1 receptor-mediated locomotor stimulation and supports inhibitory cholinergic control over dopamine-dependent behavior[2]. Mechanistically, endogenous cholinergic signaling through M4 receptors in direct-pathway striatal projection neurons promotes corticostriatal long-term depression by suppressing RGS4 activity and blocking D1-dependent long-term potentiation[3]. In disease models, enhancing M4 signaling corrected striatal plasticity deficits in L-DOPA-induced dyskinesia models, supporting M4 as a practical target for basal ganglia circuit studies[3]. Compared with related muscarinic isoforms, M1 and M4 crystal structures bound to tiotropium revealed differences in orthosteric and allosteric binding sites that contribute to subtype-selective drug design[4]. For experimental applications, M4 positive allosteric modulators potentiate acetylcholine responses without directly activating the receptor and showed antipsychotic-like activity in preclinical schizophrenia-relevant assays[5]. Xanomeline further demonstrates ligand complexity at human M4 because structural and pharmacological validation identified dual orthosteric and allosteric binding behavior[6].
References:
- [1]. van der Westhuizen ET, et al. Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias. Front Pharmacol. 2021 Jan 29;11:606656. [Content Brief]
- [2]. Gomeza J, et al. Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10483-8. [Content Brief]
- [3]. Shen W, et al. M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia. Neuron. 2015 Nov 18;88(4):762-73. [Content Brief]
- [4]. Thal DM, et al. Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature. 2016 Mar 17;531(7594):335-40. [Content Brief]
- [5]. Chan WY, et al. Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10978-83. [Content Brief]
- [6]. Burger WAC, et al. Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR. Nat Commun. 2023 Sep 6;14(1):5440. [Content Brief]
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mAChR4 Related Products (77)
Related Products (77)
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JHU37160
0 ImagesJHU37160 is a potent and brain-penetrant DREADD agonist, with EC50s of 18.5 nM and 0.2 nM for hM3Dq and hM4Di DREADDs in HEK-293 cells, respectively. JHU37160 exhibits selective [3H]Clozapine displacement from DREADDs and not from other Clozapine-binding sites in mice brain tissue.
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PD 102807
0 ImagesPD 102807 is a M4 muscarinic receptor antagonist with an IC50 of 90.7 nM. PD 102807 inhibits M1, M2, M3, M5 muscarinic receptor with IC50s of 6558.7, 3440.7, 950.0, and 7411.7 nM, respectively. Antidyskinetic effect.
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Sofpironium bromide
0 ImagesSynonyms: BBI 4000Sofpironium bromide (BBI 4000) is an anticholinergic agent used in the study of primary axillary hyperhidrosis (PAH). Sofpironium bromide reduces sweating by inhibiting M3 muscarinic receptors in eccrine glands at the application site. Sofpironium bromide also has a high afnity for the M1, M2, M4 and M5 subtypes.
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JHU37152
0 ImagesJHU37152 is a potent and brain-penetrant DREADD agonist, with EC50s of 5 nM and 0.5 nM for hM3Dq and hM4Di DREADDs in HEK-293 cells, respectively. JHU37152 exhibits selective [3H]Clozapine displacement from DREADDs and not from other Clozapine-binding sites in mice brain tissue.
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PCS1055 dihydrochloride
0 ImagesPCS1055 dihydrochloride is a potent, selective and competitive muscarinic M4 receptor antagonist with an IC50 of 18.1 nM and a Kd of 5.72 nM. PCS1055 dihydrochloride inhibits radioligand [3H]-NMS binding to the M4 receptor with a Ki of 6.5 nM. PCS1055 dihydrochloride exhibits >100-fold selectivity over M1-, M3-, and M5-receptors and 30-fold selectivity at the M2 receptor. PCS1055 dihydrochloride is also a potent AChE inhibitor with IC50 s of 22 nM and 120 nM for electric eel and human AChE, respectively.
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Clozapine hydrochloride
0 ImagesSynonyms: HF 1854 hydrochlorideClozapine hydrochloride (HF 1854 hydrochloride) is an antipsychotic used for the research of schizophrenia. Clozapine hydrochloride has high affinity for a number of neuroreceptors. Clozapine hydrochloride is a potent antagonist of dopamine D2 with a Ki of 75 nM. Clozapine hydrochloride inhibits the muscarinic M1 receptor and serotonin 5HT2A receptor with Kis of 9.5 nM and 4 nM, respectively. Clozapine hydrochloride is also a potent and selective agonist at the muscarinic M4 receptor (EC50=11 nM).
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VU6008055
0 ImagesSynonyms: AF98943VU6008055 (AF98943) is a brain-penetrant, orally active and selective muscarinic acetylcholine receptor subtype 4 (mAChR4) activator with human EC50 values of 73.4 nM. VU6008055 potentiates mAChR4 receptor activity in the presence of acetylcholine, and exhibits no activity at mAChR1, mAChR3, or mAChR5. VU6008055 can be used for the research of schizophrenia, parkinson’s disease, alzheimer’s disease.
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VU0152100
0 ImagesSynonyms: VU152100VU0152100 (VU152100) is a highly selective mAChR positive allosteric modulator (permeable to the blood-brain barrier). VU0152100 reverses Amphetamine-induced hypermotility in rats and increased levels of extracellular dopamine in nucleus accumbens and caudate-putamen. VU0152100 has good research potential in psychosis and cognitive impairment associated with mental disorders such as schizophrenia.
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VU0467485
0 ImagesSynonyms: AZ13713945VU0467485 (AZ13713945) is a potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulator (PAM). VU0467485 (AZ13713945) potentiates activity of ACh at M4 with EC50s of 26.6 nM and 78.8 nM at rat and human M4 receptors, respectively. VU0467485 (AZ13713945) shows selectivity for M4 over human and rat M1/2/3/5. VU0467485 (AZ13713945) displays moderate to high CNS penetration. VU0467485 (AZ13713945) has antipsychotic-like activity.
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PCS1055
0 ImagesPCS1055 is a selective and competitive antagonist for muscarinic M4 receptor with an IC50 of 18.1 nM and a Kd of 5.72 nM. PCS1055 inhibits radioligand [3H]-NMS binding to the M4 receptor with a Ki of 6.5 nM. PCS1055 is also an inhibitor for AChE with IC50 of 22 nM and 120 nM for electric eel and human AChE, respectively.
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Hexocyclium methylsulfate
0 ImagesHexocyclium methylsulfate is a potent mAChR antagonist with pKi values of 8.9, 7.7, 8.4, 8.8 for M1, M2, M3, and M4 subtype, respectively. Hexocyclium methylsulfate has the potential for the research of duodenal ulcer and irritable bowel syndrome.
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VU0448088
0 ImagesSynonyms: ML253VU0448088 (ML253) is a potent and cross the blood-brain barrier tricyclic muscarinic acetylcholine receptor subtype 4 (M4) positive allosteric modulator with EC50 values of 56, 176 nM for human and rat, respectively. VU0448088 has the potential for the research of psychotic.
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Direclidine
0 ImagesCat. No.: HY-159829CAS No.: 1803346-98-6Synonyms: NBI-1117568; HTL-0016878Direclidine (NBI-1117568, HTL-0016878) is a selective orthosteric agonist targeting the muscarinic acetylcholine M4 receptor, exhibiting very low affinity for M1, M2, M3, and M5 receptors. It binds to the orthosteric site of the M4 receptor in a non-covalent, competitive manner. Direclidine specifically activates the M4 receptor, inhibiting the release of acetylcholine from striatal cholinergic interneurons, thereby regulating the balance of the dopaminergic system and reducing psychiatric symptoms associated with excessive dopamine release. Direclidine can improve symptoms associated with neuropsychiatric disorders and is used in research on schizophrenia and other neuropsychiatric disorders.
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(Rac)-5-Hydroxymethyl Tolterodine hydrochloride
0 ImagesCat. No.: HY-76570ACAS No.: 250214-40-5Synonyms: (Rac)-Desfesoterodine hydrochloride; (Rac)-PNU-200577 hydrochloride(Rac)-5-Hydroxymethyl Tolterodine ((Rac)-Desfesoterodine) hydrochloride, an active metabolite of Tolterodine, is a mAChR antagonist (Ki values of 2.3 nM, 2 nM, 2.5 nM, 2.8 nM, and 2.9 nM for M1, M2, M3, M4, and M5 receptors, respectively). (Rac)-5-Hydroxymethyl Tolterodine hydrochloride can be used for overactive bladder research.
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VU10010
0 ImagesVU10010 is a potent, highly selective and allosteric M4 mAChR potentiator with an EC50 of 400 nM. VU10010 binds to an allosteric site on M4 mAChR and increases affinity for acetylcholine and coupling to G proteins. VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus.
