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
Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors.	1998 Dec	9884068
On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor.	1998 Jun	9614217
Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry.	1999 Apr	10323594
Cholinergic medication for neuroleptic-induced tardive dyskinesia.	2002	12137608
The utility of muscarinic agonists in the treatment of Alzheimer's disease.	2002 Aug-Oct	12212779
Brain proton magnetic resonance spectroscopy in Alzheimer disease: changes after treatment with xanomeline.	2002 Jan-Feb	11790638
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
The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys.	2003 Jun	12700711
The evaluation of cognitive function in the dementias: methodological and regulatory considerations.	2003 Mar	22033730
Cholinergic effects on fear conditioning II: nicotinic and muscarinic modulations of atropine-induced disruption of the degraded contingency effect.	2005 Apr	15696332
Effects of muscarinic agonists in the guinea-pig prostate.	2007 Apr	17391281
Wash-resistantly bound xanomeline inhibits acetylcholine release by persistent activation of presynaptic M(2) and M(4) muscarinic receptors in rat brain.	2007 Jul	17446301
Synthesis and evaluation of xanomeline analogs--probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor.	2008 Feb 1	17977730
Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue.	2008 Jun	18322150
Enhancement of memory function in aged mice by a novel derivative of xanomeline.	2008 Nov	18936783
Role of the central cholinergic system in the therapeutics of schizophrenia.	2008 Sep	19506725
Mechanisms of M3 muscarinic receptor regulation by wash-resistant xanomeline binding.	2009	19401618
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 Dec	20514210
Antipsychotic properties of muscarinic drugs.	2009 Jan	19122017
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 Jan 28	19111716
Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia.	2010	20954431
Confocal Analysis of Cholinergic and Dopaminergic Inputs onto Pyramidal Cells in the Prefrontal Cortex of Rodents.	2010	20589096
A novel derivative of xanomeline improves fear cognition in aged mice.	2010 Apr 5	20178835
Pharmacological evaluation of the long-term effects of xanomeline on the M(1) muscarinic acetylcholine receptor.	2010 Dec 23	21203415
Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials.	2010 Jul	20571970
Structural determinants of allosteric agonism and modulation at the M4 muscarinic acetylcholine receptor: identification of ligand-specific and global activation mechanisms.	2010 Jun 18	20406819
Update on the pharmacological treatment of Alzheimer's disease.	2010 Mar	20808547
Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation.	2010 Mar	19996296
Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors.	2010 Mar 11	20158205
Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold.	2011 Jul 14	21682298

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