Xanomeline (developmental code name LY-246,708) is a small molecule

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

agonist that was synthesized in a collaboration between

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was a Union Army officer, pharmacist, chemist, and businessman who founded Eli Lilly and Company. Lilly enlisted in the Union Army during the American Civil War and recruited a company of men to ...

and

Novo Nordisk Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, with production facilities in nine countries and affiliates or offices in five. Novo Nordisk is controlled by majority shareholder Novo Holdings A/S ...

as an investigational therapeutic being studied for the treatment of

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS) disorders. Its pharmacological action is mediated primarily through stimulation of central nervous system muscarinic M₁ and M₄ receptor subtypes. Xanomeline is a non-selective muscarinic acetylcholine receptor agonist with similar high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for all five

subtypes but has greater agonistic activity at the M₁ and M₄ subtypes. Xanomeline/trospium (Cobenfy), is a

combination medication A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

used in the treatment of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

Pharmacology

Pharmacodynamics

Muscarinic acetylcholine receptor agonist

Xanomeline is an agonist that primarily targets the muscarinic acetylcholine receptor family of five muscarinic receptor subtypes, which are designated M₁-M₅. While it binds with near identical affinity to all five of the muscarinic receptor subtypes as measured by displacement of a muscarinic radioligand, the preponderance of evidence suggests that xanomeline acts preferentially in the central nervous system as a functionally selective partial agonist at the M₁ and M₄ muscarinic receptors. It has more modest partial agonist pharmacology at the M₂, M₃ and M₅ receptors. In addition to its muscarinic acetylcholine M₁ and M₄ receptor agonism, xanomeline has been found to act as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the M₅ receptor.

Other actions

Aside from its actions at the muscarinic acetylcholine receptors, xanomeline has relatively high

for certain other

target Target may refer to: Warfare and shooting * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artille ...

s, such as various

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s. It acts specifically as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the serotonin 5-HT_1A receptor, as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the serotonin 5-HT_1B receptor, and as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Xanomeline may inhibit CYP3A4 and P-glycoprotein locally in the intestines, but does not inhibit them systemically.

Mechanism of action

Xanomeline modulates certain dopaminergic and glutamatergic circuits in the brain that can provide therapeutic benefits in patients suffering from neuropsychiatric and neurological diseases such as schizophrenia and Alzheimer's disease through stimulation primarily of central M₁ and M₄ muscarinic receptor subtypes. Muscarinic M₁ and M₄ receptors have been shown in preclinical studies to be expressed in areas important for dopamine and glutamate neural circuit regulation (e.g. frontal cortex and dorsal and ventral striatum). Xanomeline has shown

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

-like effects in various preclinical behavioral models, such as attenuation of

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

-induced

locomotor hyperactivity Locomotor activity is a measure of animal behavior which is employed in scientific research. Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in whi ...

, effects that are dependent on M₁ and M₄ receptor activation.

Pharmacokinetics

CYP2D6 significantly contributes to the metabolism of xanomeline. As a result, CYP2D6 polymorphisms are expected to affect the patient's exposure to xanomeline.

Chemistry

Xanomeline has structural and pharmacological similarities to the main psychoactive ingredient in

betel nut The areca nut ( or ) or betel nut () is the fruit of the areca palm ('' Areca catechu''). The palm is originally native to the Philippines, but was carried widely through the tropics by the Austronesian migrations and trade since at least 1 ...

arecoline Arecoline is a cholinergic agent, stimulant, and natural product, naturally occurring alkaloid found in areca nut, areca (betel) nuts of the areca palm (''Areca catechu'') found in South Asia, South and Southeast Asia. Its effects, depending on ...

, and the natural muscarinic receptor neurotransmitter, acetylcholine. Xanomeline is an achiral and lipophilic small molecule with a molecular weight of 281.4 (also known as hexyloxy-TZTP, LY246708, Lumeron, Memcor - Eli Lilly; NNC 11-0232 - Novo Nordisk; Kar-XT, Karuna Therapeutics). Xanomeline's physical chemical properties, including low molecular weight, lipophilicity, and absence of

hydrogen bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

donors, favor its entry into the brain with a high brain to plasma ratio (> 10:1).

Clinical development

Xanomeline was first discovered in a therapeutic development collaboration between Eli Lilly & Co. and Novo Nordisk pharmaceutical companies in the early 1990s. Eli Lilly led the first clinical development effort of xanomeline through a phase 2 clinical trial to test the hypothesis that it would improve cognition in patients suffering from cognitive decline observed in Alzheimer's disease, with positive results for cognitive decline and an unexpected effect against delusions and hallucination. A small placebo-controlled study in treatment-resistant schizophrenia followed, demonstrating its antipsychotic-like action. Xanomeline's development was discontinued primarily due to cholinergic side effects observed in clinical studies . Further development was enabled through a novel co-formulation strategy, xanomeline/trospium (developmental name KarXT), with the peripherally restricted muscarinic antagonist, trospium, to quell the peripheral cholinergic side effects. In March 2023, Karuna Therapeutics announced that KarXT had met its primary endpoint in a phase III trial, EMERGENT-3, and that it was submitting the drug for approval by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA). In September 2024, the combination drug was approved by the FDA.