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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 (developmental code name LY-246,708; former proposed brand names 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 high affinity for all five muscarinic acetylcholine receptor subtypes but has greater agonistic activity at the M1 and M4 subtypes.[5]

Xanomeline/trospium, sold under the brand name Cobenfy, is an approved combination drug used in the treatment of schizophrenia.[6][7] Trospium chloride is a peripherally selective non-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline's mechanism of action in this context is hypothesized to be via modulating certain neurotransmitter circuits, including acetylcholine, dopamine, and glutamate, which can provide therapeutic benefits in schizophrenia and related diseases.[8]

Pharmacology

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Pharmacodynamics

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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
ChTTooltip Choline transporter 1,390 Undefined
DATTooltip Dopamine transporter 457 Undefined
NETTooltip Norepinephrine transporter 1,630 Undefined
SERTTooltip Serotonin transporter >10,000 Undefined
Notes: Values are Ki, unless otherwise specified. The smaller the value, the more strongly the drug binds to the site. Refs: [9][10][11][12]

Muscarinic acetylcholine receptor agonist

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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.[13][14]

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.[15][16]

Other actions

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Aside from its actions at the muscarinic acetylcholine receptors, xanomeline has relatively high affinity for certain other targets, such as various serotonin receptors.[9][10][11][12] 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.[11][17]

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

Mechanism of action

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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).[8][18] Xanomeline has shown antipsychotic-like effects in various preclinical behavioral models, such as attenuation of amphetamine-induced locomotor hyperactivity,[8] effects that are dependent on M1 and M4 receptor activation.[19]

Pharmacokinetics

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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

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Xanomeline has structural and pharmacological similarities to the main psychoactive ingredient in betel 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]

Clinical development

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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.[20] A small placebo-controlled study in treatment-resistant schizophernia followed, demonstrating its antipsychotic-like action.[21]

Xanomeline's development was discontinued primarily due to cholinergic side effects observed in clinical studies [citation needed]. 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).[22] In September 2024, the combination drug was approved by the FDA.[6]

References

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  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. ^ a b "PDSP Database". UNC (in Zulu). Retrieved 26 October 2024.
  10. ^ a b Liu, Tiqing. "BindingDB BDBM50003359 5-(4-Hexyloxy-[1,2,5]thiadiazol-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". BindingDB. Retrieved 26 October 2024.
  11. ^ a b c Watson J, Brough S, Coldwell MC, Gager T, Ho M, Hunter AJ, Jerman J, Middlemiss DN, Riley GJ, Brown AM (December 1998). "Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors". Br J Pharmacol. 125 (7): 1413–1420. doi:10.1038/sj.bjp.0702201. PMC 1565721. PMID 9884068.
  12. ^ a b Bender AM, Jones CK, Lindsley CW (March 2017). "Classics in Chemical Neuroscience: Xanomeline". ACS Chem Neurosci. 8 (3): 435–443. doi:10.1021/acschemneuro.7b00001. PMID 28141924.
  13. ^ 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.
  14. ^ 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.
  15. ^ Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC (September 2022). "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". Am J Psychiatry. 179 (9): 611–627. doi:10.1176/appi.ajp.21101083. PMID 35758639.
  16. ^ Grant MK, El-Fakahany EE (October 2005). "Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor". J Pharmacol Exp Ther. 315 (1): 313–319. doi:10.1124/jpet.105.090134. PMID 16002459.
  17. ^ Odagaki Y, Kinoshita M, Ota T (September 2016). "Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes". J Psychopharmacol. 30 (9): 896–912. doi:10.1177/0269881116658989. PMID 27464743.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.
  22. ^ "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

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  • 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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