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

ABSTRACT

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 G_s- 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.

KEYWORDS:

• Allosteric modulators
• β-arrestin-biased β-agonists
• G protein biased β-agonists
• long-acting β2-agonists
• muscarinic antagonist-β2 agonist compounds

Article highlights

• There is still considerable interest in discovering highly potent and selective β₂-agonists for the symptomatic alleviation of COPD.

• Many LABAs are or have been in various stages of development, but clinical testing of these medications is either proceeding slowly or on hold.

• The current focus is to restructure the classic backbone of β₂-agonists to increase receptor affinity and drug efficacy.

• G protein and β-arrestin interaction with the β₂-AR can be selectively encouraged by ligands that stabilize unique receptor conformations. Biased agonism is the selective activation of these pathways.

• Pepducin ICL3-9, which was generated from the β₂-AR’s ICL3, displayed G_s-biased signaling that limited β-arrestin-mediated desensitization and possible tachyphylaxis from long-term usage of β₂-agonists.

• MABAs (muscarinic antagonist-β₂ agonist) are single molecules able to activate β₂-ARs and block M₃ mAChRs.

• At present, all tested MABAs have been shown to act predominantly as mAChRs 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.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.