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 | C2H2O4 |
Molecular Weight | 90.0349 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
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 |
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 |
---|---|---|---|---|
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 |
|
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 |
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 (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Other AEs: Dyspepsia, Chills... Other AEs: Dyspepsia (24.1%) Sources: Chills (36.8%) Chest pain (11.5%) increased salivation (24.1%) Nausea (51.7%) Sweating (75.9%) Syncope (12.6%) Fecal incontinence (6.9%) Vomiting (42.5%) Nausea and vomiting (8%) Dysphagia (6.9%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Chest pain | 11.5% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Syncope | 12.6% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Dyspepsia | 24.1% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
increased salivation | 24.1% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Chills | 36.8% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Vomiting | 42.5% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Nausea | 51.7% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Dysphagia | 6.9% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Fecal incontinence | 6.9% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Sweating | 75.9% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
Nausea and vomiting | 8% | 225 mg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 225 mg, 1 times / day Route: oral Route: multiple Dose: 225 mg, 1 times / day Sources: |
unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: |
PubMed
Title | Date | PubMed |
---|---|---|
On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor. | 1998 Jun |
|
Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry. | 1999 Apr |
|
From 'captive' agonism to insurmountable antagonism: demonstrating the power of analytical pharmacology. | 2001 Mar |
|
Low-affinity M(2) receptor binding state mediates mouse atrial bradycardia: comparative effects of carbamylcholine and the M(1) receptor agonists sabcomeline and xanomeline. | 2001 Mar |
|
The utility of muscarinic agonists in the treatment of Alzheimer's disease. | 2002 Aug-Oct |
|
Role of muscarinic receptors in the activation of the ventral subiculum and the consequences for dopamine release in the nucleus accumbens. | 2003 Jan 24 |
|
The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys. | 2003 Jun |
|
The evaluation of cognitive function in the dementias: methodological and regulatory considerations. | 2003 Mar |
|
Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. | 2003 Summer |
|
Systematic review of cholinergic drugs for neuroleptic-induced tardive dyskinesia: a meta-analysis of randomized controlled trials. | 2004 Nov |
|
Cholinergic effects on fear conditioning II: nicotinic and muscarinic modulations of atropine-induced disruption of the degraded contingency effect. | 2005 Apr |
|
Pharmacologic interactions between the muscarinic cholinergic and dopaminergic systems in the modulation of prepulse inhibition in rats. | 2005 Mar |
|
Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor. | 2005 Oct |
|
Effects of muscarinic agonists in the guinea-pig prostate. | 2007 Apr |
|
Long-term changes in the muscarinic M1 receptor induced by instantaneous formation of wash-resistant xanomeline-receptor complex. | 2007 Dec |
|
Wash-resistantly bound xanomeline inhibits acetylcholine release by persistent activation of presynaptic M(2) and M(4) muscarinic receptors in rat brain. | 2007 Jul |
|
Allosteric modulators of class B G-protein-coupled receptors. | 2007 Sep |
|
Allosteric modulation of muscarinic acetylcholine receptors. | 2007 Sep |
|
Importance and prospects for design of selective muscarinic agonists. | 2008 |
|
Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine. | 2008 Dec |
|
Muscarinic acetylcholine receptors: new potential therapeutic targets in antinociception and in cancer therapy. | 2008 Jun |
|
Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue. | 2008 Jun |
|
Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands. | 2009 Dec 2 |
|
Divergence of allosteric effects of rapacuronium on binding and function of muscarinic receptors. | 2009 Dec 28 |
|
Reduction in muscarinic M1-mediated hypercholinergic state and beneficial cognitive effects of muscarinic agonists in schizophrenia. | 2009 Jan |
|
Antipsychotic properties of muscarinic drugs. | 2009 Jan |
|
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 |
|
Pharmacological evaluation of the long-term effects of xanomeline on the M(1) muscarinic acetylcholine receptor. | 2010 Dec 23 |
|
Prefrontal cortex and reversion of atropine-induced disruption of the degraded contingency effect by antipsychotic agents and N-desmethylclozapine in rats. | 2010 Feb |
|
Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors. | 2010 Mar 11 |
|
Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics. | 2010 Oct |
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
by
admin
on
Edited
Sat Dec 16 08:23:49 UTC 2023
by
admin
on
Sat Dec 16 08:23:49 UTC 2023
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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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m11524
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141064-23-5
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DTXSID90596482
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