Muscarinic receptor, also known as muscarinic cholinergic/acetylcholine receptor (mAChR), belongs to the G protein-coupled receptor (GPCR) family and is found in many parts of the body, such as brain and neuromuscular junctions. The mAChR family contains five members, M1, M2, M3, M4, and M5, each with a different physiological function. Among them, M3 receptors bind to acetylcholine and can further activate downstream Gq proteins, which couple to Gq-like G proteins. This mediates an increase in intracellular calcium levels, leading to smooth muscle contraction. M3 receptor agonists are commonly used to treat gastrointestinal and bladder tone relaxation, while antagonists have some application for the treatment of chronic obstructive airway disease, irritable bowel syndrome and acute urinary incontinence.

β2-adrenergic receptors are transmembrane β-adrenergic receptors that also belong to the GPCR family. β2-agonists act on β2-adrenergic receptors to activate adenylyl cyclase, leading to increased intracellular concentrations of cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A (PKA) and Epac (Rap1 guanine nucleotide exchange factor). PKA phosphorylated proteins are involved in the regulation of smooth muscle stretching. The production of cAMP reduces the release of intracellular Ca2+, which in turn relaxes smooth muscle. Based on this,β2-agonists can act as an effective bronchodilator to relieve asthma due to muscle spasms.

CHF-6366 is a dual antagonist and agonist for these two targets.

CHF-6366 is an M3 muscarinic antagonist and a β2-adrenergic agonist (MABA) with pKi values of 10.4 and 11.4, respectively. Also, it is a weak calcium channel inhibitor with an IC50 value of approximately 50 μM. CHF-6366 (0.3 and 1 nM/kg; intratracheal administration; single dosage) can inhibit bronchoconstriction in a dose-dependent manner in guinea pigs. Moreover, it exhibits low systemic exposure and no risk of accumulation, providing a rationale for the study of chronic obstructive pulmonary disease (COPD). Therefore, this provides a theoretical basis for COPD research.

In conclusion, CHF-6366, as a potent dual M3 muscarinic antagonist and β2-adrenergic agonist, provides a direction for the treatment of respiratory-related disorders.

[1] J Med Chem. 2022 Aug 11;65(15):10233-10250.
[2] Curr Pharm Des. 2006;12(28):3573-81.
[3] Life Sci. 2021 Jan 15;265:118864.