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 (76)
Related Products (76)
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p-F-HHSiD hydrochloride
0 ImagesSynonyms: p-Fluorohexahydrosiladifenidol hydrochloridep-F-HHSiD (p-Fluorohexahydrosiladifenidol) hydrochloride is a potent and selective M3 mAChR antagonist. p-F-HHSiD hydrochloride has antagonistic effects on other subtypes of the M receptor and the alpha1-adrenoceptor. p-F-HHSiD hydrochloride 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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Direclidine citrate
0 ImagesSynonyms: NBI-1117568 citrate; HTL-0016878 citrateDireclidine (NBI-1117568, HTL-0016878) citrate is a selective orthosteric agonist targeting the muscarinic acetylcholine M4 receptor, exhibiting very low affinity for M1, M2, M3, and M5 receptors. Direclidine citrate binds to the orthosteric site of the M4 receptor in a non-covalent, competitive manner. Direclidine citrate 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 citrate 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-d14
0 ImagesCat. No.: HY-76570SCAS No.: 1185071-13-9Synonyms: (Rac)-Desfesoterodine-d14; (Rac)-PNU-200577-d14(Rac)-5-Hydroxymethyl Tolterodine-d14 is the 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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VU6002703
0 ImagesCat. No.: HY-171981CAS No.: 1934241-32-3VU6002703 (Compound 17) is a BBB-penetrable M4 mAChR positive allosteric modulator (PAM) with an EC50 of 0.6 μM for hM4. VU6002703 can be used for neuropsychiatric and rare genetic CNS disorders research.
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Milameline hydrochloride
0 ImagesCat. No.: HY-107650CAS No.: 139886-04-7Synonyms: CI 979 hydrochloride; RU 35926 hydrochlorideMilameline (CI 979; RU35926) hydrochloride is a nonselective, partical and orally active muscarinic receptor agonist that improves cognition. Milameline hydrochloride 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 hydrochloride has a higher affinity for sites [3H]CMD (IC50 = 20 nM), than [3H]QNB, (IC50 = 3059 nM). Milameline hydrochloride produces both central and peripheral cholinergic effects and reverses the cognitive deficits induced by Scopolamine (HY-N0296). Milameline hydrochloride can be used for the study of Alzheimer’s Disease.
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M1/M4 muscarinic agonist 1
0 ImagesCat. No.: HY-149702M1/M4 muscarinic agonist 1 (compound 41) is a selective muscarinic M4/M1 agonist with EC50 values of 14 and 55 nM for M4 and M1, respectively. M1/M4 muscarinic agonist 1 can be used for research on mental diseases, such as schizophrenia, delusional disorder, etc.
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Vedaclidine
0 ImagesCat. No.: HY-183144CAS No.: 141575-50-0Vedaclidine is an orally active muscarinic acetylcholine receptor (mAChR) modulator with mixed receptor activity, which activates muscarinic M2 and M4 receptors and blocks muscarinic M1, M3 and M5 receptors. Vedaclidine exerts its activity through interaction with spinal M4 muscarinic receptors, and does not induce hypothermia or excessive salivation. Vedaclidine can be used in research related to pain, neuropathic pain and inflammatory pain states.
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THRX160209
0 ImagesCat. No.: HY-189013CAS No.: 832082-44-7THRX160209 is a dual-site antagonist of the M2 muscarinic acetylcholine receptor with M2 receptor subtype selectivity. THRX160209 binds simultaneously to the orthosteric site and a spatially distinct allosteric site, competitively inhibiting receptor activation at the acetylcholine binding pocket. THRX160209 exhibits affinity for all five muscarinic receptor subtypes. THRX160209 can be used in research related to neurological disorders.
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Lu AE51090
0 ImagesLu AE51090 is selective muscarinic M1 receptor agonist with blood-brain barrier penetration. Lu AE51090 activates human M1 receptor with EC50 of 61 nM, while showing no significant agonism at M2-M5 receptors. Lu AE51090 exerts procognitive effects in mice. Lu AE51090 can be used for the study of Alzheimer’s disease (AD) and cognitive impairment associated with schizophrenia (CIAS).
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VU0476406
0 ImagesCat. No.: HY-183203CAS No.: 1451993-12-6VU0476406 is a blood-brain barrier-permeable and selective muscarinic acetylcholine receptor subtype 4 (M4) activator with human EC50 of 91.0 nM and human pEC50 of 7.04. VU0476406 potentiates endogenous acetylcholine activity at M4 receptors. VU0476406 can be used for the research of Parkinson's disease.
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VU6009453
0 ImagesCat. No.: HY-119363CAS No.: 2148929-11-5VU6009453 (compound 15q) is a brain-penetrant M4 mAChR positive allosteric modulator (PAM) with an EC50 of 383 nM. VU6009453 can be used for research on neurological diseases.
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PTAC oxalate
0 ImagesCat. No.: HY-107656CAS No.: 201939-40-4PTAC oxalate is a selective muscarinic receptor ligand. PTAC oxalate is an partial agonist of M2 and M4 but antagonist of M1, M3, and M5 (Ki values of 0.2-2.8 nM for hM1-5 in CHO cells). PTAC oxalate alleviates the mechanical allodynia on the neuropathic pain and has antidepression effects.
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M4R ligand-1
0 ImagesCat. No.: HY-189040M4R ligand-1 is a M4R ligand. M4R ligand-1 binds to the extracellular vestibular allosteric site of M4R. M4R ligand-1 can be used for the research of schizophrenia.
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M4 mAChR Modulator-2
0 ImagesCat. No.: HY-175532CAS No.: 3062458-27-6M4 mAChR Modulator-2 is an orally active, selective, brain-penetrant positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (M4 mAChR) (EC50 = 513 nM). M4 mAChR Modulator-2 exhibits high target selectivity, showing negligible affinity and low inhibition rates for non-target receptors (D1R/D2R/D3R, 5-HT subtypes, κ/δ/μ opioid receptors, H1, M1/M2) while specifically binding to M4 mAChR with a Ki of 377 nM and an inhibition rate of 62.8%. M4 mAChR Modulator-2 reverses Dizocilpine (MK-801) (HY-15084B)-induced hyperlocomotion in mice. M4 mAChR Modulator-2 can be used for the study of schizophrenia
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Muscarinic M4 modulator-1
0 ImagesCat. No.: HY-174259CAS No.: 3082186-91-9Muscarinic M4 modulator-1 is a Muscarinic M4 receptor positive allosteric modulator. Muscarinic M4 modulator-1 activates the muscarinic M4 receptor with allosteric potency EC50 s of 14 and 3 Nm in CHO-K1 cells and HEK293 cells. Muscarinic M4 modulator-1 has an antipsychotic-like activity, promising for psychiatric and/or neurological disorders research.
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LAS190792
0 ImagesCat. No.: HY-148527CAS No.: 1347232-69-2Synonyms: AZD8999LAS190792 is a bifunctional muscarinic acetylcholine receptor (mAChR) antagonist and β2-adrenergic receptor agonist. LAS190792 has a pIC50 of 8.8 against human M3 muscarinic receptor and a pIC50 of 9.1 against human β2-adrenergic receptor. LAS190792 exhibits vasodilatory and anti-inflammatory activities, and induces sustained bronchodilation in dogs. LAS190792 inhibits the release of IL-8, MMP9, IL-1β and GM-CSF from lipopolysaccharide-stimulated neutrophils. LAS190792 can be used in research related to respiratory system diseases.
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Xanomeline-NH-Boc
0 ImagesCat. No.: HY-186320CAS No.: 1018846-42-8Xanomeline-NH-Boc is a derivative of Xanomeline (HY-105182), which serves as the orthosteric pharmacophore of M1/M4 muscarinic agonist 4 (HY-187957) for activating mAChR1/4.
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Milameline
0 ImagesCat. No.: HY-135460CAS No.: 139886-32-1Synonyms: CI-979; RU35926Milameline (CI-979; RU35926) is a nonselective, partical and orally active muscarinic receptor agonist that improves cognition. Milameline 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 has a higher affinity for sites [3H]CMD (IC50 = 20 nM), than [3H]QNB, (IC50 = 3059 nM). Milameline produces both central and peripheral cholinergic effects and reverses the cognitive deficits induced by Scopolamine (HY-N0296). Milameline can be used for the study of Alzheimer’s Disease.
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Atropine hydrobromide
0 ImagesSynonyms: Tropine tropate hydrobromide; DL-Hyoscyamine hydrobromideAtropine (Tropine tropate) hydrobromide is a competitive muscarinic acetylcholine receptor (mAChR) antagonist with IC50 values of 0.39 and 0.71 nM for Human mAChR M4 and Chicken mAChR M4, respectively. Atropine hydrobromide inhibits ACh-induced relaxations in human pulmonary veins. Atropine hydrobromide can be used for research of anti-myopia and bradycardia.
