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Xanomeline

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Xanomeline
Clinical data
Pronunciation/zʌˈnɒməliːn/
zu-NOM-ə-leen
Trade namesLumeron, Memcor
Other namesLY-246,708
Routes of
administration		Oral
Drug classMuscarinic acetylcholine receptor agonist
ATC code
  • None
Identifiers
  • 3-hexoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazole
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.208.938 Edit this at Wikidata
Chemical and physical data
FormulaC14H23N3OS
Molar mass281.42 g·mol−1
3D model (JSmol)
  • CCCCCCOC1=NSN=C1C2=CCCN(C2)C
  • InChI=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
  • Key:JOLJIIDDOBNFHW-UHFFFAOYSA-N

Xanomeline (LY-246,708; Lumeron, Memcor) is a small molecule muscarinic acetylcholine receptor agonist that was first 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 affinity for all five muscarinic acetylcholine receptor subtypes (Ki = 7–22 nM) but has greater agonistic activity at the M1 and M4 subtypes.[5]

Xanomeline/trospium is an approved[6] combination drug.[7] Trospium chloride is a non-CNS penetrant non-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline's mechanism of action is hypothesized to be via rebalancing key neurotransmitter circuits, including acetylcholine, dopamine, and glutamate, which are disrupted in schizophrenia and related diseases.[8]

Chemistry

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

Pharmacology

Pharmacodynamics

Xanomeline is an agonist that primarily targets the muscarinic acetylcholine receptor family of five muscarinic receptor subtypes, which are designated M1-M5.[1] 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.[9][10]

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

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]

Central nervous system

Xanomeline regulates key dopaminergic and glutamatergic circuits in the brain that are thought to be imbalanced 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,).[8][11] Xanomeline has shown antipsychotic-like activity in various preclinical behavioral models [8] which is dependent on M1 and M4 receptor activation.[12]

Clinical development

Xanomeline was first discovered in a therapeutic development collaboration between Eli Lilly & Co. and Novo Nordisk pharmaceutical companies in the early 1990s.[2][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.[13] A small placebo-controlled study in treatment-resistant schizophernia followed, demonstrating its antipsychotic-like action.[14]

Xanomeline's development was discontinued primarily due to cholinergic side effects observed in clinical studies.[15] 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).[16] In September 2024, the conbination drug was approved by the FDA.[6]

References

  1. ^ a b c Sauerberg P, Olesen PH, Nielsen S, Treppendahl S, Sheardown MJ, Honoré T, et al. (June 1992). "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. doi:10.1021/jm00090a019. PMID 1613751.
  2. ^ a b c Bender AM, Jones CK, Lindsley CW (March 2017). "Classics in Chemical Neuroscience: Xanomeline". ACS Chemical Neuroscience. 8 (3): 435–443. doi:10.1021/acschemneuro.7b00001. PMID 28141924.
  3. ^ a b c Bymaster FP, Whitesitt CA, Shannon HE, DeLapp N, Ward JS, Calligaro DO, et al. (1997). "Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease". Drug Development Research. 40 (2): 158–170. doi:10.1002/(SICI)1098-2299(199702)40:2<158::AID-DDR6>3.0.CO;2-K. S2CID 84808093.
  4. ^ Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, et al. (May 2000). "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. doi:10.1016/s0920-9964(99)00138-3. PMID 10785583. S2CID 54259702.
  5. ^ a b c "Cobenfy (xanomeline and trospium chloride) capsules, for oral use" (PDF). Bristol-Myers Squibb. 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. ^ a b "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. ^ a b Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A (February 2021). "Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia". The New England Journal of Medicine. 384 (8): 717–726. doi:10.1056/NEJMoa2017015. PMC 7610870. PMID 33626254.
  8. ^ a b c Mirza NR, Peters D, Sparks RG (2003). "Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists". CNS Drug Reviews. 9 (2): 159–186. doi:10.1111/j.1527-3458.2003.tb00247.x. PMC 6741650. PMID 12847557.
  9. ^ Heinrich JN, Butera JA, Carrick T, Kramer A, Kowal D, Lock T, et al. (March 2009). "Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists". European Journal of Pharmacology. 605 (1–3): 53–56. doi:10.1016/j.ejphar.2008.12.044. PMID 19168056.
  10. ^ Thorn CA, Moon J, Bourbonais CA, Harms J, Edgerton JR, Stark E, et al. (March 2019). "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. doi:10.1021/acschemneuro.8b00625. PMID 30480428. S2CID 53744326.
  11. ^ Yohn SE, Conn PJ (July 2018). "Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia". Neuropharmacology. 136 (Pt C): 438–448. doi:10.1016/j.neuropharm.2017.09.012. PMC 5844786. PMID 28893562.
  12. ^ Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA (January 2009). "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. doi:10.1016/j.ejphar.2008.12.020. PMID 19111716.
  13. ^ Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, et al. (April 1997). "Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease". Archives of Neurology. 54 (4): 465–473. doi:10.1001/archneur.1997.00550160091022. PMID 9109749.
  14. ^ Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC (August 2008). "Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia". The American Journal of Psychiatry. 165 (8): 1033–1039. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778. S2CID 24308125.
  15. ^ Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, et al. (August 2008). "Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia". The American Journal of Psychiatry. 165 (8): 1033–1039. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778. S2CID 24308125.
  16. ^ "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

  • Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B (March 2007). "Towards a muscarinic hypothesis of schizophrenia". Molecular Psychiatry. 12 (3): 232–246. doi:10.1038/sj.mp.4001924. PMID 17146471. S2CID 6380981.
  • Wess J, Duttaroy A, Zhang W, Gomeza J, Cui Y, Miyakawa T, et al. (1 January 2003). "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. doi:10.3109/10606820308262. PMID 12893539.
  • Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC (September 2022). "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". The American Journal of Psychiatry. 179 (9): 611–627. doi:10.1176/appi.ajp.21101083. PMID 35758639. S2CID 250070840.
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