Xanomeline
{{Short description|Chemical compound}}
{{Use dmy dates|date=April 2025}}
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{{Infobox drug
| image = Xanomeline.svg
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| image2 = Xanomeline molecule ball.png
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| pronounce = {{IPAc-en|z|ʌ|ˈ|n|oʊ|m|ə|l|iː|n}}
{{respell|zuh|NOH|mə|leen}}
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| routes_of_administration = Oral
| class = Muscarinic acetylcholine receptor agonist
| ATC_prefix = None
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| CAS_number = 131986-45-3
| PubChem = 60809
| IUPHAR_ligand = 57
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| ChemSpiderID = 54797
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 9ORI6L73CJ
| KEGG = D06330
| ChEBI = 10056
| ChEMBL = 21536
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| synonyms = LY-246,708; LY246708; LY-246708; NNC 11-0232; Hexyloxy-TZTP
| IUPAC_name = 3-hexoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazole
| C = 14
| H = 23
| N = 3
| O = 1
| S = 1
| SMILES = CCCCCCOC1=NSN=C1C2=CCCN(C2)C
| StdInChI = 1S/C14H23N3OS/c1-3-4-5-6-10-18-14-13(15-19-16-14)12-8-7-9-17(2)11-12/h8H,3-7,9-11H2,1-2H3
| StdInChIKey = JOLJIIDDOBNFHW-UHFFFAOYSA-N
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Xanomeline (developmental code name LY-246,708) is a small molecule muscarinic acetylcholine receptor agonist that was synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system (CNS) disorders.{{cite journal | vauthors = Bender AM, Jones CK, Lindsley CW | title = Classics in Chemical Neuroscience: Xanomeline | journal = ACS Chem Neurosci | volume = 8 | issue = 3 | pages = 435–443 | date = March 2017 | pmid = 28141924 | doi = 10.1021/acschemneuro.7b00001 | url = }}{{cite journal | vauthors = Sauerberg P, Olesen PH, Nielsen S, Treppendahl S, Sheardown MJ, Honoré T, Mitch CH, Ward JS, Pike AJ, Bymaster FP | display-authors = 6 | title = Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines | journal = Journal of Medicinal Chemistry | volume = 35 | issue = 12 | pages = 2274–2283 | date = June 1992 | pmid = 1613751 | doi = 10.1021/jm00090a019 }}
Its pharmacological action is mediated primarily through stimulation of central nervous system muscarinic M1 and M4 receptor subtypes.{{Cite journal | vauthors = Bymaster FP, Whitesitt CA, Shannon HE, DeLapp N, Ward JS, Calligaro DO, Shipley LA, Buelke-Sam JL, Bodick NC, Farde L, Sheardown MJ | display-authors = 6 |year=1997 |title=Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease |journal=Drug Development Research |volume=40 |issue=2 |pages=158–170 | doi = 10.1002/(SICI)1098-2299(199702)40:2<158::AID-DDR6>3.0.CO;2-K | s2cid = 84808093 }}{{cite journal | vauthors = Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen A | display-authors = 6 | title = Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice | journal = Schizophrenia Research | volume = 42 | issue = 3 | pages = 249–259 | date = May 2000 | pmid = 10785583 | doi = 10.1016/s0920-9964(99)00138-3 | s2cid = 54259702 }} Xanomeline is a non-selective muscarinic acetylcholine receptor agonist with similar high affinity for all five muscarinic acetylcholine receptor subtypes but has greater agonistic activity at the M1 and M4 subtypes.{{cite web | title = Cobenfy (xanomeline and trospium chloride) capsules, for oral use | work = Bristol-Myers Squibb | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216158s000lbl.pdf | quote = 12.2 Pharmacodynamics Xanomeline binds to muscarinic receptors M1 to M5 with comparable affinity (Ki=10, 12, 17, 7, and 22 nM for the M1, M2, M3, M4, and M5 receptors, respectively) and exhibits higher agonist activity at the M1 and M4 receptors.}}
Xanomeline/trospium (Cobenfy), is a combination medication used in the treatment of schizophrenia.{{cite press release | title=FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia | website=U.S. Food and Drug Administration (FDA) | date=26 September 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | access-date=27 September 2024 | archive-date=27 September 2024 | archive-url=https://web.archive.org/web/20240927004824/https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | url-status=live }} {{PD-notice}}{{cite journal | vauthors = Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A | title = Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia | journal = The New England Journal of Medicine | volume = 384 | issue = 8 | pages = 717–726 | date = February 2021 | pmid = 33626254 | pmc = 7610870 | doi = 10.1056/NEJMoa2017015 }}
Pharmacology
= Pharmacodynamics =
==Muscarinic acetylcholine receptor agonist==
Xanomeline is an agonist that primarily targets the muscarinic acetylcholine receptor family of five muscarinic receptor subtypes, which are designated M1-M5. While it binds with near identical affinity to all five of the muscarinic receptor subtypes as measured by displacement of a muscarinic radioligand, the preponderance of evidence suggests that xanomeline acts preferentially in the central nervous system as a functionally selective partial agonist at the M1 and M4 muscarinic receptors. It has more modest partial agonist pharmacology at the M2, M3 and M5 receptors.{{cite journal | vauthors = Heinrich JN, Butera JA, Carrick T, Kramer A, Kowal D, Lock T, Marquis KL, Pausch MH, Popiolek M, Sun SC, Tseng E, Uveges AJ, Mayer SC | display-authors = 6 | title = Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists | journal = European Journal of Pharmacology | volume = 605 | issue = 1–3 | pages = 53–56 | date = March 2009 | pmid = 19168056 | doi = 10.1016/j.ejphar.2008.12.044 }}{{cite journal | vauthors = Thorn CA, Moon J, Bourbonais CA, Harms J, Edgerton JR, Stark E, Steyn SJ, Butter CR, Lazzaro JT, O'Connor RE, Popiolek M | display-authors = 6 | title = Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline | journal = ACS Chemical Neuroscience | volume = 10 | issue = 3 | pages = 1753–1764 | date = March 2019 | pmid = 30480428 | doi = 10.1021/acschemneuro.8b00625 | s2cid = 53744326 }}
In addition to its muscarinic acetylcholine M1 and M4 receptor agonism, xanomeline has been found to act as an antagonist or partial agonist of the M5 receptor.{{cite journal | vauthors = Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC | title = Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia | journal = Am J Psychiatry | volume = 179 | issue = 9 | pages = 611–627 | date = September 2022 | pmid = 35758639 | doi = 10.1176/appi.ajp.21101083 | url = }}{{cite journal | vauthors = Grant MK, El-Fakahany EE | title = Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor | journal = J Pharmacol Exp Ther | volume = 315 | issue = 1 | pages = 313–319 | date = October 2005 | pmid = 16002459 | doi = 10.1124/jpet.105.090134 | url = }}
==Other actions==
Aside from its actions at the muscarinic acetylcholine receptors, xanomeline has relatively high affinity for certain other targets, such as various serotonin receptors. It acts specifically as a partial agonist of the serotonin 5-HT1A receptor, as an agonist of the serotonin 5-HT1B receptor, and as an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.{{cite journal | vauthors = Odagaki Y, Kinoshita M, Ota T | title = Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes | journal = J Psychopharmacol | volume = 30 | issue = 9 | pages = 896–912 | date = September 2016 | pmid = 27464743 | doi = 10.1177/0269881116658989 | url = }}
Xanomeline may inhibit CYP3A4 and P-glycoprotein locally in the intestines, but does not inhibit them systemically.
==Mechanism of action==
Xanomeline modulates certain dopaminergic and glutamatergic circuits in the brain that can provide therapeutic benefits in patients suffering from neuropsychiatric and neurological diseases such as schizophrenia and Alzheimer's disease through stimulation primarily of central M1 and M4 muscarinic receptor subtypes. Muscarinic M1 and M4 receptors have been shown in preclinical studies to be expressed in areas important for dopamine and glutamate neural circuit regulation (e.g. frontal cortex and dorsal and ventral striatum).{{cite journal | vauthors = Mirza NR, Peters D, Sparks RG | title = Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists | journal = CNS Drug Reviews | volume = 9 | issue = 2 | pages = 159–186 | date = 2003 | pmid = 12847557 | pmc = 6741650 | doi = 10.1111/j.1527-3458.2003.tb00247.x }}{{cite journal | vauthors = Yohn SE, Conn PJ | title = Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia | journal = Neuropharmacology | volume = 136 | issue = Pt C | pages = 438–448 | date = July 2018 | pmid = 28893562 | pmc = 5844786 | doi = 10.1016/j.neuropharm.2017.09.012 }} Xanomeline has shown antipsychotic-like effects in various preclinical behavioral models, such as attenuation of amphetamine-induced locomotor hyperactivity, effects that are dependent on M1 and M4 receptor activation.{{cite journal | vauthors = Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA | title = Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice | journal = European Journal of Pharmacology | volume = 603 | issue = 1–3 | pages = 147–149 | date = January 2009 | pmid = 19111716 | doi = 10.1016/j.ejphar.2008.12.020 }}
= Pharmacokinetics =
Chemistry
Xanomeline has structural and pharmacological similarities to the main psychoactive ingredient in betel nut, arecoline, and the natural muscarinic receptor neurotransmitter, acetylcholine. Xanomeline is an achiral and lipophilic small molecule with a molecular weight of 281.4 (also known as hexyloxy-TZTP, LY246708, Lumeron, Memcor - Eli Lilly; NNC 11-0232 - Novo Nordisk; Kar-XT, Karuna Therapeutics). Xanomeline's physical chemical properties, including low molecular weight, lipophilicity, and absence of hydrogen bond donors, favor its entry into the brain with a high brain to plasma ratio (> 10:1).
Clinical development
Xanomeline was first discovered in a therapeutic development collaboration between Eli Lilly & Co. and Novo Nordisk pharmaceutical companies in the early 1990s. Eli Lilly led the first clinical development effort of xanomeline through a phase 2 clinical trial to test the hypothesis that it would improve cognition in patients suffering from cognitive decline observed in Alzheimer's disease, with positive results for cognitive decline and an unexpected effect against delusions and hallucination.{{cite journal | vauthors = Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ, Potter WZ, Paul SM | display-authors = 6 | title = Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease | journal = Archives of Neurology | volume = 54 | issue = 4 | pages = 465–473 | date = April 1997 | pmid = 9109749 | doi = 10.1001/archneur.1997.00550160091022 }} A small placebo-controlled study in treatment-resistant schizophrenia followed, demonstrating its antipsychotic-like action.{{cite journal | vauthors = Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC | title = Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia | journal = The American Journal of Psychiatry | volume = 165 | issue = 8 | pages = 1033–1039 | date = August 2008 | pmid = 18593778 | doi = 10.1176/appi.ajp.2008.06091591 | s2cid = 24308125 }}
Xanomeline's development was discontinued primarily due to cholinergic side effects observed in clinical studies {{Citation needed|date=October 2024}}. Further development was enabled through a novel co-formulation strategy, xanomeline/trospium (developmental name KarXT), with the peripherally restricted muscarinic antagonist, trospium, to quell the peripheral cholinergic side effects. In March 2023, Karuna Therapeutics announced that KarXT had met its primary endpoint in a phase III trial, EMERGENT-3, and that it was submitting the drug for approval by the US Food and Drug Administration (FDA).{{cite press release |url=https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-positive-results-phase-3-0 |title=Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia |date=20 March 2023 |website=Karuna Therapeutics |access-date=25 September 2023 |archive-date=30 July 2023 |archive-url=https://web.archive.org/web/20230730112319/https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-positive-results-phase-3-0 |url-status=live }} In September 2024, the combination drug was approved by the FDA.{{cite press release | title=FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia | website=U.S. Food and Drug Administration (FDA) | date=26 September 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | access-date=27 September 2024 | archive-date=27 September 2024 | archive-url=https://web.archive.org/web/20240927004824/https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia | url-status=live }} {{PD-notice}}
References
{{Reflist}}
Further reading
{{refbegin}}
- {{cite journal | vauthors = Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B | title = Towards a muscarinic hypothesis of schizophrenia | journal = Molecular Psychiatry | volume = 12 | issue = 3 | pages = 232–246 | date = March 2007 | pmid = 17146471 | doi = 10.1038/sj.mp.4001924 | s2cid = 6380981 }}
- {{cite journal | vauthors = Wess J, Duttaroy A, Zhang W, Gomeza J, Cui Y, Miyakawa T, Bymaster FP, McKinzie L, Felder CC, Lamping KG, Faraci FM, Deng C, Yamada M | display-authors = 6 | title = M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system | journal = Receptors & Channels | volume = 9 | issue = 4 | pages = 279–290 | date = 1 January 2003 | pmid = 12893539 | doi = 10.3109/10606820308262 }}
- {{cite journal | vauthors = Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC | title = Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia | journal = The American Journal of Psychiatry | volume = 179 | issue = 9 | pages = 611–627 | date = September 2022 | pmid = 35758639 | doi = 10.1176/appi.ajp.21101083 | s2cid = 250070840 }}
{{refend}}
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Category:Drugs developed by Novo Nordisk