Cardiac‐specific beta‐blockers and asthma: An end to fear?

Harrington, John

doi:10.1111/resp.13979

Cited by 3 publications

(4 citation statements)

References 10 publications

(25 reference statements)

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“…This cross‐reactivity has long been considered a risk factor in asthmatic patients, with deaths attributed to β‐blockers use in the very early years of their use, leading to the recommendation that non‐selective β‐blockers be avoided in asthmatic subjects. 1 , 2 Due to their high sequence and structural similarity, the molecular basis of ligand selectivity between the β‐adrenergic receptor subtypes remains to be fully understood. This has led to the suggestion that the kinetic process of ligand binding itself may contribute to ligand specificity for individual receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

“…The promiscuous binding of β‐adrenergic ligands to the closely related subtypes of the β‐adrenoceptor (e.g., the β 2 ‐adrenergic receptor) leads to commonly observed side effects such as fatigue, decreased peripheral circulation, and increased airway resistance. This cross‐reactivity has long been considered a risk factor in asthmatic patients, with deaths attributed to β‐blockers use in the very early years of their use, leading to the recommendation that non‐selective β‐blockers be avoided in asthmatic subjects 1,2 . Due to their high sequence and structural similarity, the molecular basis of ligand selectivity between the β‐adrenergic receptor subtypes remains to be fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the kinetic selectivity of drugs targeting the β₁‐adrenoceptor

Sykes

Jiménez‐Rosés

Reilly

et al. 2022

Pharmacology Res & Perspec

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In this study, we report the β 1 ‐adrenoceptor binding kinetics of several clinically relevant β 1/2 ‐adrenoceptor (β 1/2 AR) agonists and antagonists. [ 3 H]‐DHA was used to label CHO‐β 1 AR for binding studies. The kinetics of ligand binding was assessed using a competition association binding method. Ligand physicochemical properties, including logD 7.4 and the immobilized artificial membrane partition coefficient ( K IAM ), were assessed using column‐based methods. Protein Data Bank (PDB) structures and hydrophobic and electrostatic surface maps were constructed in PyMOL. We demonstrate that the hydrophobic properties of a molecule directly affect its kinetic association rate ( k on ) and affinity for the β 1 AR. In contrast to our findings at the β 2 ‐adrenoceptor, K IAM , reflecting both hydrophobic and electrostatic interactions of the drug with the charged surface of biological membranes, was no better predictor than simple hydrophobicity measurements such as clogP or logD 7.4 , at predicting association rate. Bisoprolol proved kinetically selective for the β 1 AR subtype, dissociating 50 times slower and partly explaining its higher measured affinity for the β 1 AR. We speculate that the association of positively charged ligands at the β 1 AR is curtailed somewhat by its predominantly neutral/positive charged extracellular surface. Consequently, hydrophobic interactions in the ligand‐binding pocket dominate the kinetics of ligand binding. In comparison at the β 2 AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptor's surface promoting the kinetics of ligand binding. Additionally, we reveal the potential role kinetics plays in the on‐target and off‐target pharmacology of clinically used β‐blockers.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the kinetic selectivity of drugs targeting the β₁‐adrenoceptor

Sykes

Jiménez‐Rosés

Reilly

et al. 2022

Pharmacology Res & Perspec

View full text Add to dashboard Cite

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“…The heart is not the only target for the therapeutic action of β-blockers, reflected in their use in the treatment of migraine, essential tremor, pheochromocytoma, thyrotoxicosis anxiety and the most common form of glaucoma (Baker et al, 2011;Harrington, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The promiscuous binding of β-adrenergic ligands to the closely related subtypes of the β-adrenoceptor (e.g., the β 2 -adrenergic receptor) leads to commonly observed side effects such as fatigue, decreased peripheral circulation and increased airway resistance. This cross reactivity has long been considered a risk factor in asthmatic patients, with deaths attributed to β-blockers use in the very early years of their use, leading to the recommendation that nonselective β-blockers be avoided in asthmatic subjects (Harries, 1981;Harrington, 2020).…”

Section: Introductionmentioning

confidence: 99%

Exploring the kinetic selectivity of drugs targeting the β₁-adrenoceptor

Sykes

Jiménez‐Rosés

Reilly

et al. 2021

Preprint

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In this study, we report the β1-adrenoceptor binding kinetics of several clinically relevant β1/2-adrenoceptor (β1/2AR) agonists and antagonists. We demonstrate that the physicochemical properties of a molecule directly affect its kinetic association rate (kon) and affinity for the target. In contrast to our findings at the β2AR-adrenoceptor, a drug's immobilized artificial membrane partition coefficient (KIAM), reflecting both hydrophobic and electrostatic interactions of the drug with the charged surface of biological membranes, was no better predictor than simple hydrophobicity measurements such as log P or logD7.4, characterized by a distribution between water and a non-aqueous organic phase (e.g. n-octanol) at predicting association rate. Overall, this suggests that hydrophobic interactions rather than a combination of polar and hydrophobic interactions play a more prominent role in dictating the binding of these ligands to the β1-adrenoceptor. Using a combination of kinetic data, detailed structural and physicochemical information we rationalize the above findings and speculate that the association of positively charged ligands at the β1AR is curtailed somewhat by its predominantly neutral/positive charged extracellular surface. Consequently, hydrophobic interactions in the ligand-binding pocket dominate the kinetics of ligand binding. In comparison at the β2AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptor's surface promoting the kinetics of ligand binding. Additionally, we reveal the potential role kinetics plays in the on-target and off-target pharmacology of clinically used β-blockers.

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