M1/4 muscarinic receptor
Xanomeline is a selective muscarinic M1 receptor agonist. It exhibits high affinity for muscarinic receptors: Kᵢ = 7 nM for [³H]-pirenzepine (M1 antagonist site) binding, and Kᵢ = 3 nM for [³H]-oxotremorine-M (agonist site) binding in rat brain membranes. [1]

Xanomeline oxalate stimulates phosphoinositide (PI) potential in A9 L m1 cells [1]. M) binds to the brain with Ki of 7 and 3 nM respectively[1].

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Xanomeline potently stimulated phosphoinositide (PI) hydrolysis in A9 L cell lines transfected with muscarinic m1 receptors, achieving 74% ± 15% of the maximal effect of the full agonist carbachol. [1]
Xanomeline was a potent agonist of M1 receptors in isolated rabbit vas deferens. [1]

Xanomeline oxalate strongly stimulates PI responses in vivo, and this effect is boiled by muscarinic-selective antioxidants, suggesting that it is mediated by muscarinic receptors. In mice, the ED100 of [3H]-IP accumulation in the hippocampus induced by Xanomeline oxalate was 54 μMole/kg. In the trajectory, the ED100 of [3H]-IP accumulation in the hippocampus induced by Xanomeline oxalate was 8.1 μMole/kg[1]. Animal model: Male CF1 mice weighing 18-20 g were injected with [3H]-inositol[1]. Dosage: 8.1-81 μmole/kg. Administration method: subcutaneous injection; 1 hour before sacrifice and 1 hour after administration. Results: Lithium levels increased in a dose-related manner in the hippocampus, cortex, and neostriatum, up to 130%, 75%, and 60%, respectively. and does not increase the accumulation of [3H]-IP in the brainstem. Induces salivation, tremors and hypothermia in mice with an ED50 of 13.7±0.8 μmole/kg. Animal model: Rats were injected with [3H]-inositol[1]. Dosage: 2.7-81 μmole/kg. Administration method: subcutaneous injection; 1 hour before sacrifice and 1 hour after administration. Results: [3H]-IP formation in hippocampus. Dose-dependent increase, 221% higher than lithium control.

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In mice, subcutaneous administration of xanomeline (8.1-81 μmol/kg) dose-dependently increased in vivo [³H]-inositol monophosphate ([³H]-IP) accumulation (a measure of PI hydrolysis) in the hippocampus (up to 130% above lithium control), cerebral cortex (up to 75%), and neostriatum (up to 60%), but not in the brain stem. The ED₅₀ in hippocampus was 54 μmol/kg. [1]
In rats, subcutaneous xanomeline (2.7-81 μmol/kg) also stimulated [³H]-IP accumulation in the hippocampus, with an ED₁₀₀ of 8.1 μmol/kg. [1]
The in vivo PI hydrolysis stimulation by xanomeline was blocked by centrally-acting muscarinic antagonists ((-)-scopolamine and trihexyphenidyl), confirming mediation by central muscarinic receptors. [1]

Radioligand binding assays were performed to determine the affinity of xanomeline for muscarinic receptors. Rat brain membrane preparations were incubated with [³H]-pirenzepine (1 nM) or [³H]-oxotremorine-M (3 nM) in the presence of varying concentrations of the test compound. After incubation, bound and free radioligand were separated, and radioactivity was measured to determine inhibition constants (Kᵢ) using the Cheng-Prusoff equation. [1]

The stimulation of phosphoinositide hydrolysis by xanomeline was assessed in A9 L cell lines stably transfected with muscarinic m1 receptors. Cells were labeled with [³H]-myoinositol, then stimulated with the agonist in the presence of lithium chloride to trap inositol phosphates. Reactions were stopped, water-soluble inositol phosphates were extracted and separated by anion-exchange chromatography, and radioactivity was quantified to determine agonist-induced PI hydrolysis. [1]

Male CF1 mice weighing 18-20 g are injected [³H]-myoinositol
8.1-81 μmole/kg
S.c. injections; 1 h prior to killing and 1 h after the administration

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For in vivo PI hydrolysis studies in mice, animals were first injected intracerebroventricularly with 2 μCi of [³H]-myoinositol to radiolabel phosphoinositide pools. After 24 hours, lithium chloride (10 mmol/kg, s.c.) was administered to inhibit inositol phosphate metabolism. One hour after lithium, the test compound (e.g., xanomeline) was administered subcutaneously. Animals were euthanized one hour after drug administration. Brain regions (hippocampus, cortex, neostriatum, brain stem) were dissected, homogenized, and centrifuged. [³H]-inositol monophosphates in the supernatant were isolated by anion-exchange chromatography and quantified by scintillation counting. Total radioactivity in the homogenate was also measured to calculate the percent conversion. [1]
A similar protocol was used for rats, where [³H]-myoinositol was injected intraventricularly under anesthesia. [1]
For side effect evaluation in mice, compounds were administered subcutaneously at various doses. Salivation and tremor were scored observationally (0-2 scale) 30 minutes post-dose. Hypothermia was assessed by measuring rectal temperature change. [1]

Absorption
After oral administration of salamicillin, the time to peak concentration (Tmax) is reached in approximately 2 hours. Steady-state plasma concentrations are reached 3 to 5 days after the start of treatment.
Elimination Route
Salamicillin and its metabolites are primarily excreted in the urine. Approximately 78% of the total dose is excreted in the urine, mostly as metabolites (<0.01% is the original drug). Approximately 12% of the total dose is excreted in the feces.
Volume of Distribution
The apparent volume of distribution after oral administration of salamicillin is approximately 10,800 liters.
Clearance
The apparent clearance of salamicillin is 1950 liters/hour. The renal clearance of salamicillin is 0.085 liters/hour.
Protein Binding
The protein binding rate of salamicillin in plasma is approximately 95%. Metabolites/Metabolites
Sanomeline is primarily metabolized by CYP450 enzymes (including CYP2D6, CYP2B6, CYP1A2, CYP2C9, and CYP2C19) and flavin monooxygenases (FMO1 and FMO3). Unmetabolized parenteral drug accounts for less than 0.01% of the total drug in urine.
Biological Half-Life
The half-life of sanomeline is 5 hours.

Effects during pregnancy and lactation
◉ Overview of medication use during lactation
There is currently no clinical information regarding the use of sanomalin or topiramate during lactation. Topiramate is a charged molecule and is unlikely to enter breast milk. If a mother needs to use sanomalin or topiramate, this is not a reason to discontinue breastfeeding. The infant should be monitored for vomiting, diarrhea, abnormal fetal movement, and whether weight gain is within target range.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Sanomalin At the tested dose, it induced cholinergic side effects in mice. It caused a maximum decrease in rectal temperature of 6.1 ± 0.4 °C, with an ED₅₀ of 13.7 ± 0.8 μmol/kg (subcutaneous injection). [1]
Xanomeline did not induce tremor (score 0) or salivation (score 0) at the evaluated dose of up to 81 μmol/kg. This property is more desirable than that of non-selective muscarinic agonists, which can cause significant salivation, tremor, and more severe hypothermia. [1]

[1]. Xanomeline Compared to Other Muscarinic Agents on Stimulation of Phosphoinositide Hydrolysis in Vivo and Other Cholinomimetic Effects. Brain Res. 1998 Jun 8; 795(1-2):179-90.

Xanomeline belongs to the thiadiazole and tetrahydropyridine class of compounds. It is a muscarinic receptor agonist and a serotonin receptor agonist. Xanomeline is currently being investigated in the clinical trial NCT02831231 (a pilot study comparing the efficacy of Xanomeline monotherapy versus Xanomeline in combination with topiramate). Xanomeline is a cholinergic muscarinic receptor agonist. Its mechanism of action is as a cholinergic muscarinic receptor agonist, a cytochrome P450 3A4 inhibitor, and a P-glycoprotein inhibitor. Mechanism of Action: The efficacy of Xanomeline in treating schizophrenia is thought to be related to its agonistic activity against muscarinic acetylcholine receptors M1 and M4 in the central nervous system. It has comparable affinity for muscarinic receptors M1 through M5 and exhibits relatively high agonist activity on M1 and M4 receptors. Schizophrenia is a complex disorder involving multiple neurotransmitters, including serotonin, dopamine, and acetylcholine. Traditionally, positive symptoms (such as hallucinations and delusions) are attributed to increased dopaminergic activity in the mesolimbic pathway, while negative symptoms (such as apathy and anhedonia) and cognitive impairment are attributed to decreased dopaminergic activity in the mesocortical pathway. Positive symptoms of schizophrenia are more easily treated with medication, while negative symptoms and cognitive impairment are more difficult to treat. Advances in preclinical studies and findings in clinical trials have rekindled interest in the cognitive-enhancing potential of muscarinic receptor agonists in schizophrenia, as studies have found high expression of M1 and M4 muscarinic acetylcholine receptors in cognitively related brain regions. Xanomeline, a muscarinic receptor agonist, was approved by the U.S. Food and Drug Administration (FDA) in September 2024 for the treatment of schizophrenia, becoming the first approved treatment for schizophrenia that targets muscarinic receptors rather than dopamine receptors. It was approved for marketing in combination with the muscarinic receptor antagonist topiramate, which primarily acts on peripheral muscarinic receptors and is designed to reduce the risk and severity of peripheral cholinergic adverse reactions.

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Sarnomylmide is a selective muscarinic receptor agonist (SMRA) used to treat Alzheimer's disease (AD). Clinical trials have shown that it improves cognitive function and reduces problem behaviors in AD patients. [1]
Its mechanism of action is believed to involve the selective activation of postsynaptic M1 receptors in the brain, which are coupled to the phosphatidylinositol second messenger system, which is involved in memory and cognition. [1]
Sarnomylmide's activation of M1 receptors may also affect the pathology of Alzheimer's disease by altering the processing of β-amyloid precursor protein and phosphorylation of tau protein. [1]

C16H25N3O5S

371.4518

371.151

C, 51.74; H, 6.78; N, 11.31; O, 21.54; S, 8.63

141064-23-5

Xanomeline; 131986-45-3

18920248

White to off-white solid powder

2.309

2

9

8

25

370

0

CN1CCC=C(C2=NSN=C2OCCCCCC)C1.O=C(O)C(O)=O

ZJOUESNWCLASJP-UHFFFAOYSA-N

InChI=1S/C14H23N3OS.C2H2O4/c1-3-4-5-6-10-18-14-13(15-19-16-14)12-8-7-9-17(2)11-12;3-1(4)2(5)6/h8H,3-7,9-11H2,1-2H3;(H,3,4)(H,5,6)hI=1S/C14H23N3OS.C2H2O4/c1-3-4-5-6-10-18-14-13(15-19-16-14)12-8-7-9-17(2)11-12;3-1(4)2(5)6/h8H,3-7,9-11H2,1-2H3;(H,3,4)(H,5,6)

3-hexoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazole;oxalic acid

LY-246708; LY246708; LY 246708; Memcor; NNC-110232; Hexyloxy-TZTP; HexyloxyTZTP

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~50 mg/mL (~134.6 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.73 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.73 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)