Discovering the molecular basis for ligand pharmacological activity on β-adrenoceptorsTools Bunsuz, Asuman (2023) Discovering the molecular basis for ligand pharmacological activity on β-adrenoceptors. PhD thesis, University of Nottingham.
AbstractG-protein coupled receptors (GPCRs) are the largest and most diverse family of membrane proteins in the human genome and play an important role in cellular signalling by transducing a variety of different external signals to the interior of the cell. Due to their association with numerous human diseases, GPCRs are targeted by almost 34% of approved drugs. Since the discovery of β-blockers by Sir James Black more than 60 years, β-adrenoceptors (βARs) belonging to class A G-protein coupled receptor (GPCR) family have become important therapeutic target for the treatment of cardiovascular and respiratory diseases. Despite success of existing drugs, we still need to better address the needs of patients with both asthma (treated with β2-AR agonists) and cardiovascular dysfunction (treated with β1-AR antagonists), a multi- morbidity combination of conditions that results in two-fold increase in heart failure in asthma patients on medication. This can be achieved by improving sub-type selectivity of drugs, fine-tuning their signalling properties, and increasing their ligand residency times as this would reduce their sensitivity to endogenously secreted adrenalin. Therefore, the identification of the specific and common determinants of ligand pharmacological activity on β1-ARs and β2-ARs and the investigation of the kinetic process of ligand binding to β-adrenergic subtypes are crucial to understand to the molecular mechanism of ligand selectivity between the subtypes.
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