Xanomeline Explained

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 disorders.^{[1] [2]}

Its pharmacological action is mediated primarily through stimulation of central nervous system muscarinic M₁ and M₄ receptor subtypes.^{[3] [4]} Xanomeline/trospium is currently being developed as a combination drug.^[5] 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.^[6]

Chemistry

Xanomeline has structural and pharmacological similarities to the main psychoactive ingredient in betel (areca) 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).

Pharmacology

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.^{[7] [8]}

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,).^[9] Xanomeline has shown antipsychotic-like activity in various preclinical behavioral models which is dependent on M₁ and M₄ receptor activation.^[10]

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 ^[11] and later in a small placebo-controlled study in schizophrenia. Xanomeline's development was discontinued primarily due to cholinergic side effects observed in clinical studies.^[12] Further development was enabled through a novel co-formulation strategy, xanomeline/trospium, with the peripherally restricted muscarinic antagonist, trospium, to quell the peripheral cholinergic side effects.

See also

• Alvameline
• Milameline
• Sabcomeline
• Tazomeline
• Vedaclidine

Further reading

• Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B . Towards a muscarinic hypothesis of schizophrenia . Molecular Psychiatry . 12 . 3 . 232–246 . March 2007 . 17146471 . 10.1038/sj.mp.4001924 . 6380981 .
• 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 . 6 . 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 . 12893539 . 10.3109/10606820308262 .
• Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC . Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia . The American Journal of Psychiatry . 179 . 9 . 611–627 . September 2022 . 35758639 . 10.1176/appi.ajp.21101083 . 250070840 .

Notes and References

1. Sauerberg P, Olesen PH, Nielsen S, Treppendahl S, Sheardown MJ, Honoré T, Mitch CH, Ward JS, Pike AJ, Bymaster FP . 6 . 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 . 1613751 . 10.1021/jm00090a019 .
2. Bender AM, Jones CK, Lindsley CW . Classics in Chemical Neuroscience: Xanomeline . ACS Chemical Neuroscience . 8 . 3 . 435–443 . March 2017 . 28141924 . 10.1021/acschemneuro.7b00001 .
3. Bymaster FP, Whitesitt CA, Shannon HE, DeLapp N, Ward JS, Calligaro DO, Shipley LA, Buelke-Sam JL, Bodick NC, Farde L, Sheardown MJ . 6 . 1997 . Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease . Drug Development Research . 40 . 2 . 158–170 . 10.1002/(SICI)1098-2299(199702)40:2<158::AID-DDR6>3.0.CO;2-K . 84808093 .
4. Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, Jeppesen L, Sheardown MJ, Sauerberg P, Fink-Jensen A . 6 . 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 . 10785583 . 10.1016/s0920-9964(99)00138-3 . 54259702 .
5. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A . Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia . The New England Journal of Medicine . 384 . 8 . 717–726 . February 2021 . 33626254 . 7610870 . 10.1056/NEJMoa2017015 .
6. Mirza NR, Peters D, Sparks RG . Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists . CNS Drug Reviews . 9 . 2 . 159–186 . 2003 . 12847557 . 6741650 . 10.1111/j.1527-3458.2003.tb00247.x .
7. 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 . 6 . 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 . 19168056 . 10.1016/j.ejphar.2008.12.044 .
8. Thorn CA, Moon J, Bourbonais CA, Harms J, Edgerton JR, Stark E, Steyn SJ, Butter CR, Lazzaro JT, O'Connor RE, Popiolek M . 6 . 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 . 30480428 . 10.1021/acschemneuro.8b00625 . 53744326 .
9. Yohn SE, Conn PJ . Positive allosteric modulation of M₁ and M₄ muscarinic receptors as potential therapeutic treatments for schizophrenia . Neuropharmacology . 136 . Pt C . 438–448 . July 2018 . 28893562 . 5844786 . 10.1016/j.neuropharm.2017.09.012 .
10. Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA . 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 . 19111716 . 10.1016/j.ejphar.2008.12.020 .
11. 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 . 6 . 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 . 9109749 . 10.1001/archneur.1997.00550160091022 .
12. Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC . 6 . Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia . The American Journal of Psychiatry . 165 . 8 . 1033–1039 . August 2008 . 18593778 . 10.1176/appi.ajp.2008.06091591 . 24308125 .