Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C14H23N3OS.C2H2O4 |
| Molecular Weight | 371.452 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
OC(=O)C(O)=O.CCCCCCOC1=NSN=C1C2=CCCN(C)C2
InChI
InChIKey=ZJOUESNWCLASJP-UHFFFAOYSA-N
InChI=1S/C14H23N3OS.C2H2O4/c1-3-4-5-6-10-18-14-13(15-19-16-14)12-8-7-9-17(2)11-12;3-1(4)2(5)6/h8H,3-7,9-11H2,1-2H3;(H,3,4)(H,5,6)
| Molecular Formula | C14H23N3OS |
| Molecular Weight | 281.417 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | C2H2O4 |
| Molecular Weight | 90.0349 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
Xanomeline (LY-246,708) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring. It is also known to act as a M5 receptor antagonist. Xanomeline was studied in clinical trials phase I in schizophrenia. In Phase II clinical trials in Alzheimer’s patients, xanomeline significantly improved several measures of cognitive function, yet produced unwanted side effects that limited patient compliance. The side effects seem to be associated with rapid metabolism of the alkyloxy side chain following oral administration, resulting in a nonselective, yet active compound with limited therapeutic utility. Despite a second Phase II clinical trial with a patch formulation, the liabilities of xanomeline still outweigh its benefits.
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: P08173 Gene ID: 1132.0 Gene Symbol: CHRM4 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459 |
|||
Target ID: P11229 Gene ID: 1128.0 Gene Symbol: CHRM1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459 |
|||
Target ID: P08912 Gene ID: 1133.0 Gene Symbol: CHRM5 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459 |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
|||
| Primary | Unknown Approved UseUnknown |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
8.95 ng/mL |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
XANOMELINE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: MALE food status: UNKNOWN |
|
13.81 ng/mL |
150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered: |
XANOMELINE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: MALE food status: UNKNOWN |
|
4.13 ng/mL |
75 mg 2 times / day multiple, oral dose: 75 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
XANOMELINE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: MALE food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
42.8 ng × h/mL |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
XANOMELINE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: MALE food status: UNKNOWN |
|
65.8 ng × h/mL |
150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered: |
XANOMELINE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: MALE food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
2.96 h |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
XANOMELINE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: MALE food status: UNKNOWN |
|
4.56 h |
150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered: |
XANOMELINE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: MALE food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
Other AEs: Sweating, Nausea... Other AEs: Sweating (75.9%) Sources: Nausea (51.7%) Vomiting (42.5%) Dyspepsia (24.1%) Chills (36.8%) Chest pain (11.5%) increased salivation (24.1%) Syncope (12.6%) Fecal incontinence (6.9%) Nausea and vomiting (8%) Dysphagia (6.9%) |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Chest pain | 11.5% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Syncope | 12.6% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Dyspepsia | 24.1% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| increased salivation | 24.1% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Chills | 36.8% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Vomiting | 42.5% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Nausea | 51.7% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Dysphagia | 6.9% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Fecal incontinence | 6.9% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Sweating | 75.9% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
| Nausea and vomiting | 8% | 225 mg 1 times / day multiple, oral Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| The M₁/M₄ preferring agonist xanomeline reverses amphetamine-, MK801- and scopolamine-induced abnormalities of latent inhibition: putative efficacy against positive, negative and cognitive symptoms in schizophrenia. | 2011-10 |
|
| Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold. | 2011-07-14 |
|
| Pharmacological evaluation of the long-term effects of xanomeline on the M(1) muscarinic acetylcholine receptor. | 2010-12-23 |
|
| M1 muscarinic receptor for the development of auditory cortical function. | 2010-10-22 |
|
| Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics. | 2010-10 |
|
| The M1 muscarinic receptor allosteric agonists AC-42 and 1-[1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one bind to a unique site distinct from the acetylcholine orthosteric site. | 2010-10 |
|
| Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials. | 2010-07 |
|
| Structural determinants of allosteric agonism and modulation at the M4 muscarinic acetylcholine receptor: identification of ligand-specific and global activation mechanisms. | 2010-06-18 |
|
| The antipsychotic potential of muscarinic allosteric modulation. | 2010-05 |
|
| A novel derivative of xanomeline improves fear cognition in aged mice. | 2010-04-05 |
|
| Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors. | 2010-03-11 |
|
| Update on the pharmacological treatment of Alzheimer's disease. | 2010-03 |
|
| Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation. | 2010-03 |
|
| Modulation of prepulse inhibition through both M(1) and M (4) muscarinic receptors in mice. | 2010-02 |
|
| Prefrontal cortex and reversion of atropine-induced disruption of the degraded contingency effect by antipsychotic agents and N-desmethylclozapine in rats. | 2010-02 |
|
| Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia. | 2010 |
|
| Confocal Analysis of Cholinergic and Dopaminergic Inputs onto Pyramidal Cells in the Prefrontal Cortex of Rodents. | 2010 |
|
| Divergence of allosteric effects of rapacuronium on binding and function of muscarinic receptors. | 2009-12-28 |
|
| Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands. | 2009-12-02 |
|
| Mechanisms of action of antipsychotic drugs of different classes, refractoriness to therapeutic effects of classical neuroleptics, and individual variation in sensitivity to their actions: Part I. | 2009-12 |
|
| Immediate and delayed consequences of xanomeline wash-resistant binding at the M3 muscarinic receptor. | 2009-06 |
|
| Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists. | 2009-03-01 |
|
| 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. | 2009-01-28 |
|
| Reduction in muscarinic M1-mediated hypercholinergic state and beneficial cognitive effects of muscarinic agonists in schizophrenia. | 2009-01 |
|
| Antipsychotic properties of muscarinic drugs. | 2009-01 |
|
| Mechanisms of M3 muscarinic receptor regulation by wash-resistant xanomeline binding. | 2009 |
|
| Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine. | 2008-12 |
|
| Enhancement of memory function in aged mice by a novel derivative of xanomeline. | 2008-11 |
|
| Effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain; comparison with effects of 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584) and N-desmethylclozapine. | 2008-10-31 |
|
| Role of the central cholinergic system in the therapeutics of schizophrenia. | 2008-09 |
|
| A novel derivative of xanomeline improved memory function in aged mice. | 2008-08 |
|
| Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. | 2008-08 |
|
| Muscarinic acetylcholine receptors: new potential therapeutic targets in antinociception and in cancer therapy. | 2008-06 |
|
| Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue. | 2008-06 |
|
| Role of M1 receptor in the locomotion behavior of the African mole-rat (Cryptomys sp). | 2008-03 |
|
| Synthesis and evaluation of xanomeline analogs--probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor. | 2008-02-01 |
|
| Importance and prospects for design of selective muscarinic agonists. | 2008 |
|
| Long-term changes in the muscarinic M1 receptor induced by instantaneous formation of wash-resistant xanomeline-receptor complex. | 2007-12 |
|
| Allosteric modulators of class B G-protein-coupled receptors. | 2007-09 |
|
| Allosteric modulation of muscarinic acetylcholine receptors. | 2007-09 |
|
| Wash-resistantly bound xanomeline inhibits acetylcholine release by persistent activation of presynaptic M(2) and M(4) muscarinic receptors in rat brain. | 2007-07 |
|
| Effects of muscarinic agonists in the guinea-pig prostate. | 2007-04 |
|
| Evaluation of [18F]fluoroxanomeline {5-{4-[(6-[18F]fluorohexyl)oxy]-1,2,5-thiadiazol-3-yl}-1-methyl-1,2,3,6-tetrahydropyridine} in muscarinic knockout mice. | 2007-02 |
|
| Long-term wash-resistant effects of brief interaction of xanomeline at the M1 muscarinic receptor. | 2006-12-13 |
|
| Interaction studies of multiple binding sites on m4 muscarinic acetylcholine receptors. | 2006-08 |
|
| Differences in kinetics of xanomeline binding and selectivity of activation of G proteins at M(1) and M(2) muscarinic acetylcholine receptors. | 2006-08 |
|
| Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor. | 2005-10 |
|
| The evaluation of cognitive function in the dementias: methodological and regulatory considerations. | 2003-03 |
|
| Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. | 1998-12 |
|
| On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor. | 1998-06 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT02831231
Xanomeline tartrate 75 mg TID, for 225 mg total daily dose Placebo, TID
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459
CHO cells, stably expressing the human M5 muscarinic acetylcholine receptor were incubated for 1 h at 37°C in the absence or presence of xanomeline (1, 10, or 30 μM). Further experiments were designed to assess whether xanomeline, a partial agonist, can act as an antagonist to a full agonist at the M5 receptor. Cells were incubated for 1 h with 3 μM carbachol in the absence or in the presence of increasing concentrations of xanomeline. Xanomeline was able to antagonize the ability of carbachol to stimulate PI production in a concentration-dependent manner down to the level of maximal receptor activation by xanomeline alone.
| Substance Class |
Chemical
Created
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Edited
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| Record UNII |
JF5A0PK3G5
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| Record Status |
Validated (UNII)
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| Record Version |
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