Muscarinic type 1 and type 4 receptors; mAChR1; mAChR4

The mean firing rate increased overall in response to xanomeline (0.1~10 μM; CNS4U). The functionality of M1 receptors in neurons produced from hiPSCs is demonstrated by xanomeline. When xanomeline (>1 μM) attaches to receptors, it activates them for an extended amount of time, which keeps the M current from flowing [1].

In certain monkeys, xanomeline (0.5~3 mg/kg; sc; 1~3 hours) induces vomiting and salivation[3]. Xanomeline exhibits properties resembling those of an antipsychotic and functional dopamine antagonist. Xanomeline prevents extrapyramidal side effects while blocking behaviors brought on by D-amphetamine and ()-apomorphine[3].

Animal/Disease Models: Male Cebus apella monkeys
Doses: 0.5~3 mg/kg
Route of Administration: Sc; 1~3 hrs (hours)
Experimental Results: Induced salivation and vomiting in some monkeys.

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.
Excretion
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 excreted 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 sanometrine or topiramate during lactation. Topiramate is a charged molecule and is unlikely to enter breast milk. If a mother needs to use sanometrine or topiramate, this is not a reason to stop 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.

[1]. Role of Kv7.2/Kv7.3 and M1 muscarinic receptors in the regulation of neuronal excitability in hiPSC-derived neurons. Eur J Pharmacol. 2019;858:172474.

[2]. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033-1039.

[3]. The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys. Neuropsychopharmacology. 2003;28(6):1168-1175.

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 is used in combination with trospium, a muscarinic receptor antagonist that primarily acts on peripheral muscarinic receptors, to reduce the risk and severity of peripheral cholinergic adverse reactions.

C14H23N3OS

281.42

281.156

C, 59.75; H, 8.24; N, 14.93; O, 5.69; S, 11.39

131986-45-3

Xanomeline tartrate;152854-19-8;Xanomeline oxalate;141064-23-5

60809

White to yellow solid powder

1.101 g/cm3

397ºC at 760 mmHg

193.9ºC

1.64E-06mmHg at 25°C

1.537

3.154

0

5

7

19

298

0

CCCCCCOC1=NSN=C1C2=CCCN(C2)C

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

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

XANOMELINE; 131986-45-3; LY-246708; LY 246708; LY246708;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 (177.67 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.88 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.

---

Solubility in Formulation 2: 2.5 mg/mL (8.88 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (8.88 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.

---

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