XANOMELINE

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 Search

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459 | https://www.ncbi.nlm.nih.gov/pubmed/12212779

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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Muscarinic acetylcholine receptor M4 86 Target ID: P08173 Gene ID: 1132.0 Gene Symbol: CHRM4 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459	Agonist 2678
Muscarinic acetylcholine receptor M1 169 Target ID: P11229 Gene ID: 1128.0 Gene Symbol: CHRM1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459	Agonist 2678
Muscarinic acetylcholine receptor M5 62 Target ID: P08912 Gene ID: 1133.0 Gene Symbol: CHRM5 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/16002459	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Alzheimer’s disease 272 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28141924	Primary		Phase II 1132	Unknown Approved Use Unknown
Schizophrenia 298 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28141924	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
4.13 ng/mL EXPERIMENT https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_40	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 EXPERIMENT https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_40	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 EXPERIMENT https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_40	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 EXPERIMENT https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_40	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 EXPERIMENT https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_40	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.96 h EXPERIMENT https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_40	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 EXPERIMENT https://link.springer.com/chapter/10.1007/978-1-4615-8149-9_40	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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749	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: https://pubmed.ncbi.nlm.nih.gov/9109749

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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749
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: https://pubmed.ncbi.nlm.nih.gov/9109749	unhealthy, ADULT n = 87 Health Status: unhealthy Condition: Alzheimer disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 87 Sources: https://pubmed.ncbi.nlm.nih.gov/9109749

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2C8 693 FMO1 17 FMO3 67 CYP2C19 991 CYP1A2 1054 CYP2A6 543 CYP2E1 667 CYP2B6 664

Drug as victim

Target	Modality	Activity
CYP2A6 543	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	likely
CYP2C8 693	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	likely
CYP2E1 667	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	likely
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	yes
CYP2B6 664	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	yes
FMO1 17	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	yes
FMO3 67	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY114854	https://www.001chemical.com/chem/search?q=DY114854
1PlusChem LLC	1P001GAT	https://www.1pchem.com/search?query=1P001GAT
AK Scientific	4161AH	https://aksci.com/item_detail.php?cat=4161AH
AK Scientific	G849	https://aksci.com/item_detail.php?cat=G849
Ambeed	A114713	http://www.ambeed.com/search/Search.html?keyword=A114713
Angene	AGN-PC-0WHAOK	http://www.angenechemical.com/productshow/AGN-PC-0WHAOK.html
AstaTech	C72296	http://astatechinc.com/CPSResult.php?CRNO=C72296
BLD Pharm	BD448272	http://www.bldpharm.com/search/Search.html?keyword=BD448272
BOC Sciences	131986-45-3	http://www.bocsci.com/description.asp?cas=131986-45-3
BOC Sciences	141064-23-5	http://www.bocsci.com/description.asp?cas=141064-23-5
Cayman Chemical	10790	http://www.caymanchem.com/app/template/Product.vm/catalog/10790
Chem Scene	CS-2124	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-2124
Combi-Blocks	QJ-7407	http://www.combi-blocks.com/cgi-bin/find.cgi?QJ-7407
Combi-Blocks	QV-5368	http://www.combi-blocks.com/cgi-bin/find.cgi?QV-5368
KeyOrganics	DS-15663	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=DS-15663
Lab Network	LN00198999	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN00198999
Lab Network	LN01315811	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01315811
Matrix Scientific	97008	http://www.matrixscientific.com/097008.html
MedChem Express	HY-13410	https://www.medchemexpress.com/search.html?q=HY-13410&ft=&fa=&fp=
MolPort	MolPort-023-276-854	https://www.molport.com/shop/molecule-link/MolPort-023-276-854
MolPort	MolPort-023-334-334	https://www.molport.com/shop/molecule-link/MolPort-023-334-334
Molcore	MC114854	http://www.molcore.com/CatMC114854.html
Molnova	M11712	https://www.molnova.com/en/serch-list.html?keywords=M11712
MuseChem	I012049	https://www.musechem.com/product/I012049.html
ShangHai Biochempartner	BCP11070	http://www.biochempartner.com/search_BCP11070
Tetrahedron	TS34352	http://www.thsci.com/search.do?q=TS34352
Tocris	3569	https://www.tocris.com/search.php?Type=QuickSearch&Value=3569
Toronto Research Chemicals	H298183	https://www.trc-canada.com/product-detail/?CatNum=H298183
Vesino Industrial Co Ltd	VP14766	http://www.vsnchem.com/search.do?a=s&psize=20&q=VP14766
Wonderchem	WD052ZH	http://www.wonder-chem.com/search.html?text=WD052ZH
eMolecules	29703210	https://orderbb.emolecules.com/search/#?query=29703210
eMolecules	300436560	https://orderbb.emolecules.com/search/#?query=300436560
eMolecules	44471106	https://orderbb.emolecules.com/search/#?query=44471106
eNovation Chemicals	D515415	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D515415&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-2400708987	https://mcule.com/MCULE-2400708987/
mcule	MCULE-8362695048	https://mcule.com/MCULE-8362695048/

PubMed

Title	Date	PubMed
On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor.	1998 Jun	9614217
From 'captive' agonism to insurmountable antagonism: demonstrating the power of analytical pharmacology.	2001 Mar	11236130
Cholinergic medication for neuroleptic-induced tardive dyskinesia.	2002	12137608
Role of muscarinic receptors in the activation of the ventral subiculum and the consequences for dopamine release in the nucleus accumbens.	2003 Jan 24	12559371
Systematic review of cholinergic drugs for neuroleptic-induced tardive dyskinesia: a meta-analysis of randomized controlled trials.	2004 Nov	15610922
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 Feb	17307122
Allosteric modulation of muscarinic acetylcholine receptors.	2007 Sep	19305798
A novel derivative of xanomeline improved memory function in aged mice.	2008 Aug	18668154
Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue.	2008 Jun	18322150
Role of M1 receptor in the locomotion behavior of the African mole-rat (Cryptomys sp).	2008 Mar	18431815
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 Oct 31	18771666
Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists.	2009 Mar 1	19168056
Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia.	2010	20954431
Update on the pharmacological treatment of Alzheimer's disease.	2010 Mar	20808547
Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics.	2010 Oct	20676613
M1 muscarinic receptor for the development of auditory cortical function.	2010 Oct 22	20964868

Patents

Sample Use Guides

In Vivo Use Guide

Xanomeline tartrate 75 mg TID, for 225 mg total daily dose Placebo, TID

Route of Administration: Oral

In Vitro Use Guide

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.

Name

Type

Language

XANOMELINE

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