Advances in adrenergic receptors for the treatment of chronic obstructive pulmonary disease: 2023 update

Introduction: Strong scientific evidence and large experience support the use of β2-agonists for the symptomatic alleviation of COPD. Therefore, there is considerable effort in discovering highly potent and selective β2-agonists. Areas covered: Recent research on novel β2-agonists for the treatment of COPD. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to September 2023.” Expert opinion: Compounds that preferentially activate a Gs- or β-arrestin-mediated signaling pathway via β- adrenoceptors (ARs) are more innovative. Pepducins, which target the intracellular region of β2-AR to modulate receptor signaling output, have the most interesting profile from a pharmacological point of view. They stabilize the conformation of the β2-AR and influence its signaling by interacting with the intracellular receptor-G protein interface. New bifunctional drugs called muscarinic antagonist-β2 agonist (MABA), which have both muscarinic receptor (mAChR) antagonism and β2-agonist activity in the same molecule, are a new opportunity. However, all tested compounds have been shown to act predominantly as mAChR antagonists or β2-agonists. An intriguing idea is to utilize allosteric modulators that bind to β2-ARs at sites different than those bound by orthosteric ligands to augment or reduce the signaling transduced by the orthosteric ligand.