Clozapine N-oxide(CNO),34233-69-7,IC-0197501

Clozapine N-oxide(CNO) is a potent dopamine antagonist and also a potent and selective muscarinic M4 receptor (EC50=11 nM) agonist[5，6].Clozapine N-oxide also is a major metabolite of Clozapine and a human muscarinic designer receptors (DREADDs) agonist[1,2]. Clozapine N-oxide activates the DREADD receptor hM3Dq and hM4Di. Clozapine N-oxide(CNO) is a pharmacologically inert molecule that lacks a significant (<1 μm) affinity for the receptor[3]. Clozapine N-oxide(CNO) is highly bioavailable in rodents and humans[4]
Clozapine N-oxide(CNO) significantly reduces the density of the 5-HT2 receptor in rat cortical cells, A significant decrease was found in primary cortical cells for 5-HT(2) receptor density and 5-HT(2A) receptor mRNA levels[7].
In both β-R-q and β-R-s Tg mice, Clozapine N-oxide(CNO) treatment resulted in a dose-dependent decrease in blood glucose levels and increased plasma insulin concentrations, demonstrating that the degree of β cell G protein signaling could be titrated according to the Clozapine N-oxide(CNO) dose administered[8].Oral Clozapine N-oxide(CNO) administration via drinking water to mice expressing rM3Dq in pancreatic β-cells led to robust metabolic phenotypes, indicating that significant amounts of Clozapine N-oxide(CNO) are absorbed from the gastrointestinal tract[9].It created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug Clozapine N-oxide (CNO).Local field potential and single-neuron recordings revealed that peripheral administration of Clozapine N-oxide(CNO) activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased locomotion, stereotypy, and limbic seizures[10].