Xanomeline

Xanomeline
Clinical data
Pronunciation/zʌˈnɒməliːn/
zu-NOM-ə-leen
Trade namesLumeron, Memcor
Other namesLY-246,708
Routes of
administration		Oral
Drug classMuscarinic acetylcholine receptor agonist
ATC code
  • None
Identifiers
  • 3-hexoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazole
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.208.938 Edit this at Wikidata
Chemical and physical data
FormulaC14H23N3OS
Molar mass281.42 g·mol−1
3D model (JSmol)
  • CCCCCCOC1=NSN=C1C2=CCCN(C2)C
  • 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
  • Key:JOLJIIDDOBNFHW-UHFFFAOYSA-N

Xanomeline (developmental code name LY-246,708; former proposed brand names Lumeron, Memcor) is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system (CNS) disorders.[1][2]

Its pharmacological action is mediated primarily through stimulation of central nervous system muscarinic M1 and M4 receptor subtypes.[3][4] Xanomeline is a non-selective muscarinic acetylcholine receptor agonist with similar high affinity for all five muscarinic acetylcholine receptor subtypes but has greater agonistic activity at the M1 and M4 subtypes.[5]

Xanomeline/trospium, sold under the brand name Cobenfy, is an approved combination drug used in the treatment of schizophrenia.[6][7] Trospium chloride is a peripherally selective non-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline's mechanism of action in this context is hypothesized to be via modulating certain neurotransmitter circuits, including acetylcholine, dopamine, and glutamate, which can provide therapeutic benefits in schizophrenia and related diseases.[8]

  1. ^ Sauerberg P, Olesen PH, Nielsen S, Treppendahl S, Sheardown MJ, Honoré T, et al. (June 1992). "Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines". Journal of Medicinal Chemistry. 35 (12): 2274–2283. doi:10.1021/jm00090a019. PMID 1613751.
  2. ^ Bender AM, Jones CK, Lindsley CW (March 2017). "Classics in Chemical Neuroscience: Xanomeline". ACS Chemical Neuroscience. 8 (3): 435–443. doi:10.1021/acschemneuro.7b00001. PMID 28141924.
  3. ^ Bymaster FP, Whitesitt CA, Shannon HE, DeLapp N, Ward JS, Calligaro DO, et al. (1997). "Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease". Drug Development Research. 40 (2): 158–170. doi:10.1002/(SICI)1098-2299(199702)40:2<158::AID-DDR6>3.0.CO;2-K. S2CID 84808093.
  4. ^ Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, et al. (May 2000). "Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice". Schizophrenia Research. 42 (3): 249–259. doi:10.1016/s0920-9964(99)00138-3. PMID 10785583. S2CID 54259702.
  5. ^ "Cobenfy (xanomeline and trospium chloride) capsules, for oral use" (PDF). Bristol-Myers Squibb. 12.2 Pharmacodynamics Xanomeline binds to muscarinic receptors M1 to M5 with comparable affinity (Ki=10, 12, 17, 7, and 22 nM for the M1, M2, M3, M4, and M5 receptors, respectively) and exhibits higher agonist activity at the M1 and M4 receptors.
  6. ^ "FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia". U.S. Food and Drug Administration (FDA) (Press release). 26 September 2024. Archived from the original on 27 September 2024. Retrieved 27 September 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ^ Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A (February 2021). "Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia". The New England Journal of Medicine. 384 (8): 717–726. doi:10.1056/NEJMoa2017015. PMC 7610870. PMID 33626254.
  8. ^ Mirza NR, Peters D, Sparks RG (2003). "Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists". CNS Drug Reviews. 9 (2): 159–186. doi:10.1111/j.1527-3458.2003.tb00247.x. PMC 6741650. PMID 12847557.