xanomeline   Click here for help

GtoPdb Ligand ID: 57

Synonyms: LY 246708
PDB Ligand
Compound class: Synthetic organic
Comment: Xanomeline is a muscarinic receptor agonist, with preference for the M1 and M4 receptor subtypes [2,8,12]. It also has antagonist activity at 5-HT2 receptors, and agonist activity at 5-HT1 receptors [10]. Xanomeline was investigated for potential to improve cognition in Alzheimer's disease (AD) patients, but activation of muscarinic receptors in the gastrointestinal tract caused severe nausea and diarrhoea, and this adverse effect led to discontinuation of xanomeline's clinical development for AD.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 3
Hydrogen bond donors 0
Rotatable bonds 7
Topological polar surface area 66.49
Molecular weight 281.16
XLogP 3.34
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CCCCCCOc1nsnc1C1=CCCN(C1)C
Isomeric SMILES CCCCCCOc1nsnc1C1=CCCN(C1)C
InChI 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
InChI Key JOLJIIDDOBNFHW-UHFFFAOYSA-N
References
1. Breier A, Brannan SK, Paul SM, Miller AC. (2023)
Evidence of trospium's ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results.
Psychopharmacology (Berl), 240 (5): 1191-1198. [PMID:37036495]
2. Christopoulos A, Pierce TL, Sorman JL, El-Fakahany EE. (1998)
On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor.
Mol Pharmacol, 53 (6): 1120-30. [PMID:9614217]
3. Correll CU, Abi-Dargham A, Howes O. (2022)
Emerging Treatments in Schizophrenia.
J Clin Psychiatry, 83 (1). [PMID:35172048]
4. Correll CU, Angelov AS, Miller AC, Weiden PJ, Brannan SK. (2022)
Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia.
Schizophrenia (Heidelb), 8 (1): 109. [PMID:36463237]
5. Dean B, Scarr E. (2020)
Muscarinic M1 and M4 receptors: Hypothesis driven drug development for schizophrenia.
Psychiatry Res, 288: 112989. [PMID:32315882]
6. Grant MK, El-Fakahany EE. (2005)
Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor.
J Pharmacol Exp Ther, 315 (1): 313-9. [PMID:16002459]
7. Kaul I, Sawchak S, Correll CU, Kakar R, Breier A, Zhu H, Miller AC, Paul SM, Brannan SK. (2024)
Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial.
Lancet, 403 (10422): 160-170. [PMID:38104575]
8. McDonald JK, van der Westhuizen ET, Pham V, Thompson G, Felder CC, Paul SM, Thal DM, Christopoulos A, Valant C. (2022)
Biased Profile of Xanomeline at the Recombinant Human M4 Muscarinic Acetylcholine Receptor.
ACS Chem Neurosci, 13 (8): 1206-1218. [PMID:35380782]
9. Powers AS, Pham V, Burger WAC, Thompson G, Laloudakis Y, Barnes NW, Sexton PM, Paul SM, Christopoulos A, Thal DM et al.. (2023)
Structural basis of efficacy-driven ligand selectivity at GPCRs.
Nat Chem Biol, 19 (7): 805-814. [PMID:36782010]
10. Watson J, Brough S, Coldwell MC, Gager T, Ho M, Hunter AJ, Jerman J, Middlemiss DN, Riley GJ, Brown AM. (1998)
Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors.
Br J Pharmacol, 125 (7): 1413-20. [PMID:9884068]
11. Weiden PJ, Breier A, Kavanagh S, Miller AC, Brannan SK, Paul SM. (2022)
Antipsychotic Efficacy of KarXT (Xanomeline-Trospium): Post Hoc Analysis of Positive and Negative Syndrome Scale Categorical Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study.
J Clin Psychiatry, 83 (3). [PMID:35552528]
12. Wood MD, Murkitt KL, Ho M, Watson JM, Brown F, Hunter AJ, Middlemiss DN. (1999)
Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry.
Br J Pharmacol, 126 (7): 1620-4. [PMID:10323594]