XANOMELINE TARTRATE

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C14H23N3OS.C4H6O6
Molecular Weight	431.504
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O[C@H]([C@@H](O)C(O)=O)C(O)=O.CCCCCCOC1=NSN=C1C2=CCCN(C)C2

InChI

InChIKey=SJSVWTMVMBGIHQ-LREBCSMRSA-N

InChI=1S/C14H23N3OS.C4H6O6/c1-3-4-5-6-10-18-14-13(15-19-16-14)12-8-7-9-17(2)11-12;5-1(3(7)8)2(6)4(9)10/h8H,3-7,9-11H2,1-2H3;1-2,5-6H,(H,7,8)(H,9,10)/t;1-,2-/m.1/s1

HIDE SMILES / InChI

Molecular Formula	C4H6O6
Molecular Weight	150.0868
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

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

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 85 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 2662
Muscarinic acetylcholine receptor M1 168 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 2662
Muscarinic acetylcholine receptor M5 61 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 2760

Conditions

Condition	Modality	Targets	Highest Phase	Product
Alzheimer’s disease 268 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28141924	Primary		Phase II 1144	Unknown Approved Use Unknown
Schizophrenia 295 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28141924	Primary		Phase I 424	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 1709	substrate 1010	substrate 1193

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2C8 688 FMO1 16 FMO3 66 CYP2C19 985 CYP1A2 1032 CYP2A6 523 CYP2E1 648 CYP2B6 660

Drug as victim

Target	Modality	Activity
CYP2A6 523	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	likely
CYP2C8 688	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	likely
CYP2E1 648	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	likely
CYP2C19 985	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP2C9 1010	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP2D6 1193	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP3A4 1709	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	minor
CYP1A2 1032	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	yes
CYP2B6 660	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	yes
FMO1 16	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10497134/	yes
FMO3 66	substrate 3326 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
Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry.	1999 Apr	10323594
From 'captive' agonism to insurmountable antagonism: demonstrating the power of analytical pharmacology.	2001 Mar	11236130
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	11181912
Cholinergic medication for neuroleptic-induced tardive dyskinesia.	2002	12137608
Muscarinic receptors as a target for drugs treating schizophrenia.	2002 Apr	12769625
The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys.	2003 Jun	12700711
[Selective M1 muscarinic agonists: failure of therapeutic strategy against Alzheimer's disease or inappropriate tactics?].	2003 May	12714934
Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists.	2003 Summer	12847557
Role of receptor protein and membrane lipids in xanomeline wash-resistant binding to muscarinic M1 receptors.	2004 Jan	14569060
Interaction studies of multiple binding sites on m4 muscarinic acetylcholine receptors.	2006 Aug	16709648
A novel derivative of xanomeline improved memory function in aged mice.	2008 Aug	18668154
Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia.	2008 Aug	18593778
Pharmacological assessment of m1 muscarinic acetylcholine receptor-gq/11 protein coupling in membranes prepared from postmortem human brain tissue.	2008 Jun	18322150
Role of the central cholinergic system in the therapeutics of schizophrenia.	2008 Sep	19506725
Antipsychotic properties of muscarinic drugs.	2009 Jan	19122017
Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists.	2009 Mar 1	19168056
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
Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials.	2010 Jul	20571970
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 Oct	20660086
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.

Substance Class	Chemical Created by `admin` on `Wed Jul 05 23:22:23 UTC 2023` Edited by `admin` on `Wed Jul 05 23:22:23 UTC 2023`
Record UNII	B80W7AUT8R
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

XANOMELINE TARTRATE

Official Name

English

XANOMELINE (+)-L-HYDROGEN TARTRATE

Common Name

English

3-(4-(HEXYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE (-)-(+)-TARTRATE (1:1)

Systematic Name

English

PYRIDINE, 3-(4-(HEXYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYL-, (R-(R*,R*))-2,3-DIHYDROXYBUTANEDIOATE (1:1)

Systematic Name

English

LY-246708 TARTRATE

Code

English

Xanomeline tartrate [WHO-DD]

Common Name

English

XANOMELINE (+)-L-HYDROGEN TARTRATE [MI]

Common Name

English

XANOMELINE TARTRATE [USAN]

Common Name

English

LY246708 TARTRATE

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C47796