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 beta(2)-agonists for the symptomatic alleviation of COPD. Therefore, there is considerable effort in discovering highly potent and selective beta(2)-agonists.Areas covered: Recent research on novel beta(2)-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 G(s)- or beta-arrestin-mediated signaling pathway via beta- adrenoceptors (ARs) are more innovative. Pepducins, which target the intracellular region of beta(2)-AR to modulate receptor signaling output, have the most interesting profile from a pharmacological point of view. They stabilize the conformation of the beta(2)-AR and influence its signaling by interacting with the intracellular receptor-G protein interface. New bifunctional drugs called muscarinic antagonist-beta(2) agonist (MABA), which have both muscarinic receptor (mAChR) antagonism and beta(2)-agonist activity in the same molecule, are a new opportunity. However, all tested compounds have been shown to act predominantly as mAChR antagonists or beta(2)-agonists. An intriguing idea is to utilize allosteric modulators that bind to beta(2)-ARs at sites different than those bound by orthosteric ligands to augment or reduce the signaling transduced by the orthosteric ligand.