Xanomeline
(Synonyms: 占诺美林,LY-246708) 目录号 : GC63260
Potent agonist of muscarinic receptors
Cas No.:131986-45-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Muscarinic receptors are G protein-coupled acetylcholine receptors that play diverse roles. Xanomeline (oxalate) is a potent agonist of muscarinic acetylcholine receptors (EC50 values are 0.3, 92.5, 5, 52, and 42 nM for M1, M2, M3, M4, and M5, respectively).1 It has antipsychotic-
1.Heinrich, J.N., Butera, J.A., Carrick, T., et al.Pharmacological comparison of muscarinic ligands: Historical versus more recent muscarinic M1-preferring receptor agonistsEur. J. Pharmacol.605(1-3)53-56(2009) 2.Stanhope, K.J., Mirza, N.R., Dickerdike, M.J., et al.The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the ratJ. Pharmacol. Exp. Ther.299(2)782-792() 3.Andersen, M.B., Fink-Jensen, A., Peacock, L., et al.The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeysNeuropsychopharmacology28(6)1168-1175(2003) 4.Messer, W.S., Jr.The utility of muscarinic agonists in the treatment of Alzheimer's diseaseJ. Mol. Neurosci.19(1-2)187-193(2002)
| Cas No. | 131986-45-3 | SDF | |
| 别名 | 占诺美林,LY-246708 | ||
| 分子式 | C14H23N3OS | 分子量 | 281.42 |
| 溶解度 | DMSO : 50 mg/mL (177.67 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.5534 mL | 17.767 mL | 35.5341 mL |
| 5 mM | 0.7107 mL | 3.5534 mL | 7.1068 mL |
| 10 mM | 0.3553 mL | 1.7767 mL | 3.5534 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data
Innov Clin Neurosci 2022 Oct-Dec;19(10-12):43-47.PMID:36591549doi
Xanomeline, a cholinergic agonist, was initially evaluated for the treatment of Alzheimer's disease and schizophrenia. However, drug development was stopped due to the severe cholinergic adverse effects. In recent years, Xanomeline has been explored, along with trospium, a peripheral cholinergic antagonist, for schizophrenia. Xanomeline acts primarily as an M1/M4 agonist and might lead to improvement in all symptom types of schizophrenia. Due to its role as an antimuscarinic agent, trospium is expected to reduce the adverse effects of Xanomeline. In initial studies, this combination seems to be promising in the treatment of schizophrenia. The most common side effects of this combination included constipation, dry mouth, and nausea. This article summarizes the present status of combination Xanomeline and trospium in schizophrenia.
Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists
CNS Drug Rev 2003 Summer;9(2):159-86.PMID:12847557DOI:10.1111/j.1527-3458.2003.tb00247.x.
Binding studies initially suggested that the muscarinic agonist, Xanomeline, was a subtype selective muscarinic M(1) receptor agonist, and a potential new treatment for Alzheimer's disease. However, later in vitro and in vivo functional studies suggest that this compound is probably better described as a subtype selective M(1)/M(4) muscarinic receptor agonist. This subtype selectivity profile has been claimed to explain the limited classical cholinomimetic side effects, particularly gastrointestinal, seen with Xanomeline in animals. However, in both healthy volunteers and Alzheimer's patients many of these side effects have been reported for Xanomeline and in the patient population this led to a >50% discontinuation rate. Clearly, the preclinical studies have not been able to predict this adverse profile of Xanomeline, and this suggests that either Xanomeline is not as subtype selective as predicted from preclinical research or that there are differences between humans and animals with regard to muscarinic receptors. Nevertheless, in Alzheimer's patients Xanomeline dose-dependently improves aspects of behavioral disturbance and social behavior including a reduction in hallucinations, agitation, delusions, vocal outbursts and suspiciousness. The effects on cognition are not as robust and mainly seen at the highest doses tested. These effects in Alzheimer's patients have given impetus to the suggestion that muscarinic agonists have potential antipsychotic effects. The current review assesses the antipsychotic profile of Xanomeline within the framework of the limited clinical studies with cholinergic agents in man, and the preclinical research on Xanomeline using various models commonly used for the assessment of new antipsychotic drugs. In general, Xanomeline has an antipsychotic-like profile in various dopamine models of psychosis and this agrees with the known interactions between the cholinergic and dopaminergic systems in the brain. Moreover, current data suggests that the actions of Xanomeline at the M(4) muscarinic receptor subtype might mediate its antidopaminergic effects. Particularly intriguing are studies showing that Xanomeline, even after acute administration, selectively inhibits the firing of mesolimbic dopamine cells relative to dopamine cell bodies projecting to the striatum. This data suggest that Xanomeline would have a faster onset of action compared to current antipsychotics and would not induce extrapyramidal side effects. The preclinical data on the whole are promising for an antipsychotic-like profile. If in a new formulation (i.e., transdermal) Xanomeline has less adverse effects, this drug may be valuable in the treatment of patients with psychosis.
Classics in Chemical Neuroscience: Xanomeline
ACS Chem Neurosci 2017 Mar 15;8(3):435-443.PMID:28141924DOI:10.1021/acschemneuro.7b00001.
Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer's disease (AD) patients. Despite the compound's promising initial clinical results, dose-limiting side effects limited further clinical development. While Xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound's unique M1/M4-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of Xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M1 or M4. This Review will address Xanomeline's overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.
Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia
N Engl J Med 2021 Feb 25;384(8):717-726.PMID:33626254DOI:10.1056/NEJMoa2017015.
Background: The muscarinic receptor agonist Xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of Xanomeline. The efficacy and safety of combined Xanomeline and trospium in patients with schizophrenia are unknown. Methods: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of Xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. Results: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. Conclusions: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).
New Antipsychotic Medications in the Last Decade
Curr Psychiatry Rep 2021 Nov 29;23(12):87.PMID:34843030DOI:10.1007/s11920-021-01298-w.
Purpose of review: Over the last ten years, the treatment of psychosis has seen a near explosion of creative development in both novel agents and new delivery modalities. The current review summarizes these developments over the past decade (2011-2020). We performed a systematic review utilizing PubMed and PsychInfo with the aim of identifying all the RCT and related analyses in adults with psychosis (schizophrenia and mania). Recent findings: We identified 11 significant developments: the introduction of new antipsychotics cariprazine, brexpiprazole, lumateperone, and pimavanserin; introduction of new delivery methods: subcutaneous long-acting risperidone, aripiprazole lauroxil, transdermal asenapine, and inhaled loxapine; and the introduction of new approaches such as olanzapine/samidorphan for olanzapine-associated weight gain, examination of the TAAR1 agonist SEP 363,856 as a test of concept, and the combination of Xanomeline/Trospium, an M1 and M4 muscarinic receptor agonist in conjunction with a peripheral anticholinergic. Last decade has seen a tremendous development in second-generation antipsychotics which provides unprecedented treatment options for clinicians in treating psychosis.