Xanomeline

image2	Xanomeline molecule ball.png
width2	233
routes of administration	Oral
class	Muscarinic acetylcholine receptor agonist
atc prefix	None
cas number	131986-45-3
pubchem	60809
iuphar ligand	57
drugbank	DB15357
chemspiderid	54797
unii	9ORI6L73CJ
kegg	D06330
chebi	10056
chembl	21536
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

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]

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.[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]

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]

Muscarinic acetylcholine receptor agonist

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

Mechanism of action

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]

References

Classics in Chemical Neuroscience: Xanomeline ACS Chem Neurosci, March 2017^

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, June 1992^

Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease Drug Development Research, 1997^

Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice Schizophrenia Research, May 2000^

Cobenfy (xanomeline and trospium chloride) capsules, for oral use Bristol-Myers Squibb^

FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia U.S. Food and Drug Administration (FDA), 26 September 2024, retrieved 27 September 2024^

Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia The New England Journal of Medicine, February 2021^

PDSP Database UNC, retrieved 26 October 2024^

Tiqing Liu. 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^

Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors Br J Pharmacol, December 1998^

Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists European Journal of Pharmacology, March 2009^

Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline ACS Chemical Neuroscience, March 2019^

Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia Am J Psychiatry, September 2022^

Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor J Pharmacol Exp Ther, October 2005^

Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes J Psychopharmacol, September 2016^

Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists CNS Drug Reviews, 2003^

Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia Neuropharmacology, July 2018^

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, January 2009^

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease Archives of Neurology, April 1997^

Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia The American Journal of Psychiatry, August 2008^

Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia Karuna Therapeutics, 20 March 2023, retrieved 25 September 2023^

Xanomeline

Pharmacology

Pharmacodynamics

Muscarinic acetylcholine receptor agonist

Other actions

Mechanism of action

Muscarinic acetylcholine receptor agonist

Other actions

Mechanism of action

Pharmacokinetics

Chemistry

Clinical development

Further reading

References