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].
Verweise:
- [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 Verwandte Produkte (76)
Verwandte Produkte (76)
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M4 mAChR Modulator-1
0 ImagesArt. -Nr.: HY-159177M4 mAChR Modulator-1 (compound 23i) is a M4 mAChR positive allosteric modulator (PAM). M4 mAChR Modulator-1 exhibits significantly greater cooperativity with ACh in β-arrestin recruitment over G protein activation. M4 mAChR Modulator-1 displays weak PAM effect in G protein-mediated responses, but strong PAM effect in β-arrestin recruitment.
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VU6015241
0 ImagesArt. -Nr.: HY-182384CAS. Nr.: 2264025-00-3VU6015241 is a selective, blood-brain barrier-permeable M4 mAChR Antagonist with a Ki value of 43.3 nM. VU6015241 is used for the research of dystonia and related movement disorders.
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5-Hydroxymethyl Tolterodine-d14 formate
0 ImagesArt. -Nr.: HY-76570S15-Hydroxymethyl Tolterodine-d14 (formate) is deuterium labeled (Rac)-5-Hydroxymethyl Tolterodine. (Rac)-5-Hydroxymethyl Tolterodine ((Rac)-Desfesoterodine), 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 can be used for overactive bladder research.
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Bethanechol-d6 chloride
0 ImagesArt. -Nr.: HY-B0406ASSynonyms: Carbamyl-β-methylcholine-d6 chlorideBethanechol-d6 (chloride) is the deuterium labeled Bethanechol chloride. Bethanechol chloride (Carbamyl-β-methylcholine chloride), a parasympathomimetic agent, is a mAChR agonist that exerts its effects via directly stimulating the mAChR (M1, M2, M3, M4, and M5) of the parasympathetic nervous system.
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VU6009048
0 ImagesArt. -Nr.: HY-180421CAS. Nr.: 2226116-93-2VU6009048 is a CNS-penetrant human M4 muscarinic acetylcholine receptor (mAChR4) positive allosteric modulator. VU6009048 can be used for the research of parkinson’s disease, huntington’s disease, schizophrenia.
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Milameline hydroiodide
0 ImagesArt. -Nr.: HY-107650ASynonyms: CI 979 hydroiodide; RU 35926 hydroiodideMilameline (CI 979; RU35926) hydroiodide is a nonselective, partical and orally active muscarinic receptor agonist that improves cognition. Milameline hydroiodide has equal affinity for different subtypes of human muscarinic receptors with IC50 of 1.3 µM for M1-, 1.1 µM for M2-, 1.5 µM for M3-, and 1.9 µM for M4-muscarinic receptors. Milameline hydroiodide has a higher affinity for sites [3H]CMD (IC50 = 20 nM), than [3H]QNB, (IC50 = 3059 nM). Milameline hydroiodide produces both central and peripheral cholinergic effects and reverses the cognitive deficits induced by Scopolamine (HY-N0296). Milameline hydroiodide can be used for the study of Alzheimer’s Disease.
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M1/M4 muscarinic agonist 4
0 ImagesArt. -Nr.: HY-187957M1/M4 muscarinic agonist 4 is a dual-site muscarinic acetylcholine receptor ligand with potent agonistic activity at M1/M4 muscarinic acetylcholine receptors. M1/M4 muscarinic agonist 4 activates M1R to induce phosphorylation of ERK1/2, and activates M4R to induce GαoB protein activation as well as ERK1/2 phosphorylation. M1/M4 muscarinic agonist 4 exhibits higher binding affinity for M4R than for other muscarinic receptors, while its binding affinity for the W435A mutant M4R is reduced. M1/M4 muscarinic agonist 4 can be used in the research of schizophrenia.
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Clozapine dihydrochloride
0 ImagesArt. -Nr.: HY-14539BCAS. Nr.: 2711603-38-0Synonyms: HF 1854 dihydrochlorideClozapine (HF 1854) dihydrochloride is an antipsychotic used for the research of schizophrenia. Clozapine has high affinity for a number of neuroreceptors. Clozapine is a potent antagonist of dopamine D2 with a Ki of 75 nM. Clozapine inhibits the muscarinic M1 receptor and serotonin 5HT2A receptor with Kis of 9.5 nM and 4 nM, respectively. Clozapine is also a potent and selective agonist at the muscarinic M4 receptor (EC50=11 nM).
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M1/M2/M4 muscarinic agonist 1
0 ImagesArt. -Nr.: HY-149704CAS. Nr.: 2640109-42-6M1/M2/M4 muscarinic agonist 1 (Compound 42) is a muscarinic M4/M1/M2 agonist with EC50 values of 6.5, 26 and 210 nM for M4/M1/M2, respectively. M1/M2/M4 muscarinic agonist 1 can be used for research on mental diseases, such as schizophrenia, delusion, etc.
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p-F-HHSiD
0 ImagesArt. -Nr.: HY-137388CAS. Nr.: 116679-83-5Synonyms: p-Fluorohexahydrosiladifenidolp-F-HHSiD (p-Fluorohexahydrosiladifenidol) is a potent and selective M3 mAChR antagonist. p-F-HHSiD has antagonistic effects on other subtypes of the M receptor and the alpha1-adrenoceptor. p-F-HHSiD can be used for the researches of cancer, metabolic, neurological and cardiovascular disease such as, colon cancer, Alzheimer’s disease and diabetes.
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Sofpironium tosylate
0 ImagesArt. -Nr.: HY-167849CAS. Nr.: 2409055-48-5Synonyms: BBI-4000 tosylateSofpironium (BBI 4000) tosylate is an anticholinergic agent used in the study of primary axillary hyperhidrosis (PAH). Sofpironium tosylate reduces sweating by inhibiting M3 muscarinic receptors in eccrine glands at the application site. Sofpironium tosylate also has a high afnity for the M1, M2, M4 and M5 subtypes.
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AE9C90CB
0 ImagesArt. -Nr.: HY-134971CAS. Nr.: 893426-98-7AE9C90CB, muscarinic receptor antagonist, has greater affinity for M3 muscarinic receptors with pKi of 9.90 and was 20-fold more selective for M3 than for M2 muscarinic receptors.
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Atropine oxide hydrochloride
0 ImagesArt. -Nr.: HY-122510ACAS. Nr.: 4574-60-1Synonyms: Atropine oxidation hydrochlorideAtropine Oxide (Atropine oxidation) hydrochloride, a derivative of Atropine, acts as a competitive antagonist to the muscarinic acetylcholine receptors M1, M2, M3, M4, and M5, and is utilized in the treatment of specific nerve agent and pesticide poisonings.
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rac-Fesoterodine-d14 fumarate
0 ImagesArt. -Nr.: HY-70053SCAS. Nr.: 1185237-08-4(Rac)-Fesoterodine-d14 fumarate is a labelled racemic Fesoterodine. Fesoterodine is an orally active, nonsubtype selective, competitive muscarinic receptor (mAChR) antagonist with pKivalues of 8.0, 7.7, 7.4, 7.3, 7.5 for M1, M2, M3, M4, M5 receptors, respectively. Fesoterodine is used for the overactive bladder (OAB).
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Arecaidine-propargyl ester
0 ImagesArt. -Nr.: HY-183853CAS. Nr.: 35516-99-5Arecaidine-propargyl ester is a selective M2 muscarinic receptor agonist with blood-brain barrier permeability, with a pKi of 5.91 for hm1, 7.06 for hm2, 6.07 for hm3, 6.01 for hm4, and 6.03 for hm5. Arecaidine-propargyl ester stimulates central and peripheral muscarinic receptors. Arecaidine-propargyl ester increases intracellular ROS, induces DNA damage and Apoptosis, and upregulates the expression of MnSOD and SIRT1. Arecaidine-propargyl ester reduces sympathetic nerve outflow, induces dose-dependent hypotension, and triggers negative chronotropic effects at high peripheral doses. Arecaidine-propargyl ester can be used in research related to Alzheimer's disease and glioblastoma.
