U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C14H23N3OS
Molecular Weight 281.417
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of XANOMELINE

SMILES

CCCCCCOC1=NSN=C1C2=CCCN(C)C2

InChI

InChIKey=JOLJIIDDOBNFHW-UHFFFAOYSA-N
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

HIDE SMILES / InChI

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.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P08173
Gene ID: 1132.0
Gene Symbol: CHRM4
Target Organism: Homo sapiens (Human)
Target ID: P11229
Gene ID: 1128.0
Gene Symbol: CHRM1
Target Organism: Homo sapiens (Human)
Target ID: P08912
Gene ID: 1133.0
Gene Symbol: CHRM5
Target Organism: Homo sapiens (Human)
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
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

AUC

ValueDoseCo-administeredAnalytePopulation
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

T1/2

ValueDoseCo-administeredAnalytePopulation
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

Doses

DosePopulationAdverse 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%)
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%)
Sources:
AEs

AEs

AESignificanceDosePopulation
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:
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors.
1998 Dec
On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor.
1998 Jun
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 muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat.
2001 Nov
Brain proton magnetic resonance spectroscopy in Alzheimer disease: changes after treatment with xanomeline.
2002 Jan-Feb
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 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
Differences in kinetics of xanomeline binding and selectivity of activation of G proteins at M(1) and M(2) muscarinic acetylcholine receptors.
2006 Aug
Long-term changes in the muscarinic M1 receptor induced by instantaneous formation of wash-resistant xanomeline-receptor complex.
2007 Dec
Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine.
2008 Dec
Role of M1 receptor in the locomotion behavior of the African mole-rat (Cryptomys sp).
2008 Mar
Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands.
2009 Dec 2
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
Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold.
2011 Jul 14
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 Oct
Patents

Patents

Sample Use Guides

Xanomeline tartrate 75 mg TID, for 225 mg total daily dose Placebo, TID
Route of Administration: Oral
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 Sat Dec 16 17:14:10 GMT 2023
Edited
by admin
on Sat Dec 16 17:14:10 GMT 2023
Record UNII
9ORI6L73CJ
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
XANOMELINE
INN   MART.   MI   USAN   WHO-DD  
USAN   INN  
Official Name English
LY-246708 FREE BASE
Code English
PYRIDINE, 3-(4-(HEXYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYL-
Systematic Name English
XANOMELINE [MI]
Common Name English
LY-246708
Code English
XANOMELINE [USAN]
Common Name English
LY246708
Code English
xanomeline [INN]
Common Name English
Xanomeline [WHO-DD]
Common Name English
XANOMELINE [MART.]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C47796
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
Code System Code Type Description
ChEMBL
CHEMBL21536
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
WIKIPEDIA
Xanomeline
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
EVMPD
SUB00093MIG
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
DRUG BANK
DB15357
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
USAN
EE-69
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
FDA UNII
9ORI6L73CJ
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
CAS
131986-45-3
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
INN
7125
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
SMS_ID
100000079349
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
NCI_THESAURUS
C152926
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
MERCK INDEX
m11524
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY Merck Index
CHEBI
10056
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
PUBCHEM
60809
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
EPA CompTox
DTXSID60157286
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
DRUG CENTRAL
3652
Created by admin on Sat Dec 16 17:14:12 GMT 2023 , Edited by admin on Sat Dec 16 17:14:12 GMT 2023
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
TARGET -> AGONIST
TARGET -> AGONIST
SALT/SOLVATE -> PARENT
TARGET -> AGONIST
TARGET -> AGONIST
Related Record Type Details
ACTIVE MOIETY