Chemistry:Xanomeline

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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.[1][2]

Its pharmacological action is mediated primarily through stimulation of central nervous system muscarinic M1 and M4 receptor subtypes.[3][4] 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.[5]

Xanomeline/trospium (Cobenfy), is a combination medication used in the treatment of schizophrenia.[5][6][7]

Pharmacology

Pharmacodynamics

Xanomeline binding affinities
Target Affinity (Ki, nM) Species
M1 7.9–82 Human
M2 8.1–724 Human
M3 7.8–40 Human
M4 11–72 Human
M5 9.3–80 Human
nACh (neuronal) >10,000 Undefined
nACh (muscle) >10,000 Undefined
5-HT1A 63 Human
5-HT1B 50 Human
5-HT1D 6.3 Human
5-HT1E 2,512 Human
5-HT1F 316 Human
5-HT2A 126 Human
5-HT2B 20 Human
5-HT2C 40 Human
5-HT3 >10,000 Undefined
5-HT4 251 Porcine
5-HT5A ND ND
5-HT6 1,259 Human
5-HT7 126 Human
α1-Adrenergic 2020 Rat
α2-Adrenergic 1000 Rat
α2B-Adrenergic 1,585 Human
D2 1,000 Human
D3 398 Human
H1 398 Rat
ChT 1,390 Undefined
DAT 457 Undefined
NET 1,630 Undefined
SERT >10,000 Undefined
Notes: Values are Ki, unless otherwise specified. The smaller the value, the more strongly the drug binds to the site. Refs: [8][9][10][1]

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.[2] 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.[11][12]

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.[1][13][14]

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.[8][9][10][1] 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.[10][15]

Xanomeline may inhibit CYP3A4 and P-glycoprotein locally in the intestines, but does not inhibit them systemically.[5]

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).[16][17] Xanomeline has shown antipsychotic-like effects in various preclinical behavioral models, such as attenuation of amphetamine-induced locomotor hyperactivity,[16] effects that are dependent on M1 and M4 receptor activation.[18]

Pharmacokinetics

CYP2D6 significantly contributes to the metabolism of xanomeline. As a result, CYP2D6 polymorphisms are expected to affect the patient's exposure to xanomeline.[5]

Chemistry

Xanomeline has structural and pharmacological similarities to the main psychoactive ingredient in betel nut, arecoline, and the natural muscarinic receptor neurotransmitter, acetylcholine.[2][1] 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).[3]

Clinical development

Xanomeline was first discovered in a therapeutic development collaboration between Eli Lilly & Co. and Novo Nordisk pharmaceutical companies in the early 1990s.[1][3] 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.[19] A small placebo-controlled study in treatment-resistant schizophrenia followed, demonstrating its antipsychotic-like action.[20]

Xanomeline's development was discontinued primarily due to cholinergic side effects observed in clinical studies . 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.[7] 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).[21] In September 2024, the combination drug was approved by the FDA.[6]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Classics in Chemical Neuroscience: Xanomeline". ACS Chem Neurosci 8 (3): 435–443. March 2017. doi:10.1021/acschemneuro.7b00001. PMID 28141924. 
  2. ↑ 2.0 2.1 2.2 "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 of Medicinal Chemistry 35 (12): 2274–2283. June 1992. doi:10.1021/jm00090a019. PMID 1613751. 
  3. ↑ 3.0 3.1 3.2 "Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease". Drug Development Research 40 (2): 158–170. 1997. doi:10.1002/(SICI)1098-2299(199702)40:2<158::AID-DDR6>3.0.CO;2-K. 
  4. ↑ "Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice". Schizophrenia Research 42 (3): 249–259. May 2000. doi:10.1016/s0920-9964(99)00138-3. PMID 10785583. 
  5. ↑ 5.0 5.1 5.2 5.3 "Cobenfy (xanomeline and trospium chloride) capsules, for oral use". Bristol-Myers Squibb. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216158s000lbl.pdf. "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." 
  6. ↑ 6.0 6.1 "FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia". U.S. Food and Drug Administration (FDA) (Press release). 26 September 2024. Archived from the original on 27 September 2024. Retrieved 27 September 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ↑ 7.0 7.1 "Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia". The New England Journal of Medicine 384 (8): 717–726. February 2021. doi:10.1056/NEJMoa2017015. PMID 33626254. 
  8. ↑ 8.0 8.1 "PDSP Database" (in zu). https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=xanomeline&kiAllRadio=all&doQuery=Submit+Query. 
  9. ↑ 9.0 9.1 Liu, Tiqing. "BindingDB BDBM50003359 5-(4-Hexyloxy-[1,2,5thiadiazol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine; oxalic acid::5-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1-methyl-1,2,3,6-tetrahydropyridine::CHEMBL21536::CHEMBL73149::LY 246708::Xanomeline"]. https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50003359. 
  10. ↑ 10.0 10.1 10.2 "Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors". Br J Pharmacol 125 (7): 1413–1420. December 1998. doi:10.1038/sj.bjp.0702201. PMID 9884068. 
  11. ↑ "Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists". European Journal of Pharmacology 605 (1–3): 53–56. March 2009. doi:10.1016/j.ejphar.2008.12.044. PMID 19168056. 
  12. ↑ "Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline". ACS Chemical Neuroscience 10 (3): 1753–1764. March 2019. doi:10.1021/acschemneuro.8b00625. PMID 30480428. 
  13. ↑ "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". Am J Psychiatry 179 (9): 611–627. September 2022. doi:10.1176/appi.ajp.21101083. PMID 35758639. 
  14. ↑ "Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor". J Pharmacol Exp Ther 315 (1): 313–319. October 2005. doi:10.1124/jpet.105.090134. PMID 16002459. 
  15. ↑ "Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes". J Psychopharmacol 30 (9): 896–912. September 2016. doi:10.1177/0269881116658989. PMID 27464743. 
  16. ↑ 16.0 16.1 "Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists". CNS Drug Reviews 9 (2): 159–186. 2003. doi:10.1111/j.1527-3458.2003.tb00247.x. PMID 12847557. 
  17. ↑ "Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia". Neuropharmacology 136 (Pt C): 438–448. July 2018. doi:10.1016/j.neuropharm.2017.09.012. PMID 28893562. 
  18. ↑ "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". European Journal of Pharmacology 603 (1–3): 147–149. January 2009. doi:10.1016/j.ejphar.2008.12.020. PMID 19111716. 
  19. ↑ "Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease". Archives of Neurology 54 (4): 465–473. April 1997. doi:10.1001/archneur.1997.00550160091022. PMID 9109749. 
  20. ↑ "Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia". The American Journal of Psychiatry 165 (8): 1033–1039. August 2008. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778. 
  21. ↑ "Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia". Karuna Therapeutics (Press release). 20 March 2023. Archived from the original on 30 July 2023. Retrieved 25 September 2023.

Further reading

  • "Towards a muscarinic hypothesis of schizophrenia". Molecular Psychiatry 12 (3): 232–246. March 2007. doi:10.1038/sj.mp.4001924. PMID 17146471. 
  • "M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system". Receptors & Channels 9 (4): 279–290. 1 January 2003. doi:10.3109/10606820308262. PMID 12893539. 
  • "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". The American Journal of Psychiatry 179 (9): 611–627. September 2022. doi:10.1176/appi.ajp.21101083. PMID 35758639. 



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