Molecular Mechanism of the β 3 AR Agonist Activity of a β-Blocker.

Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The β ₃ AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of β ₁ AR and β ₂ AR. Interestingly, several β-blockers, which are antagonists of the β ₁ ARs and β ₂ ARs, have been reported to exhibit agonist activity at the β ₃ AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of β ₃ AR agonists with improved selectivity and reduced off-target effects. In this work, we determined the structures of human β ₃ AR in complex with the endogenous agonist epinephrine or with a synthetic β ₃ AR agonist carazolol, which is also a high-affinity β-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D ^3.32 directly contribute to carazolol's distinct activities as an antagonist for the β ₂ AR and an agonist for the β ₃ AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective β ₃ AR agonists, paving the way for new therapeutic opportunities.
(© 2024 Wiley-VCH GmbH.)