Muscarinic M3 receptors are a subtype of Muscarinic acetylcholine receptors (mAChRs). Specifically, mAChRs is acetylcholine receptor, which forms a G-protein-coupled receptor complex in the cell membrane of some neurons and other cells. They play a variety of roles, including acting as the main terminal receptors for acetylcholine stimulation released by postganglionic fibers in the parasympathetic nervous system. Besides, M3 receptors are coupled with GQ-like G proteins and up-regulate phospholipase C. So it regulates inositol triphosphate and intracellular calcium as signaling pathways.
Moreover, direct stimulation of vascular smooth muscle M3 mediates vasoconstriction in the pathological process of vascular endothelium destruction. Furthermore, the Muscarinic M3 receptor regulates pancreatic insulin secretion, which is an important target to understand the mechanism of type 2 diabetes. Meanwhile, the M3 receptor is expressed in airway smooth muscle, submucous gland, and vascular endothelium. In M3R–/– knockout mice, the contraction of airway smooth muscle cells in response to ACh is mainly mediated by the M3 receptor. Here, we will introduce a selective and competitive muscarinic M3 receptor antagonist, CHF5407.
CHF5407 is a Muscarinic M3-Receptor Antagonist.
How does CHF5407 work on the target? Let’s study it together. In the beginning, CHF5407 is a selective, long-acting and competitive muscarinic M3 receptor antagonist. Nonetheless, CHF5407 shows subnanomolar affinities for human muscarinic M1 (hM1), M2 (hM2), and M3 (hM3) receptors. Interestingly, CHF5407 shows a prolonged antibronchospastic activity.
In the second place, CHF5407 has a very slow dissociation from M3 receptors (hM3; t1/2=166 min). Importantly, CHF5407 has markedly short-acting at M2 receptors (hM2; t1/2=31 min). Particularly, CHF5407 produces a long-lasting inhibition of M3 receptor-mediated contractile responses to carbachol in the guinea pig isolated trachea and human isolated bronchus.
Last but not the least, CHF5407 with 0.1-1 nmol/kg by intratracheally exerted a dose-dependent and potent inhibition of ACh-induced (20 g/kg; i.v.) bronchospasm. Obviously, CHF5407 has an ED50 value of 0.15 nmol/kg in guinea pigs (450-550 g).
All in all, CHF5407 is a selective, long-acting and competitive muscarinic M3 receptor antagonist.
G Villetti, et al. J Pharmacol Exp Ther. 2010 Dec;335(3):622-35.