Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists

Lumb, Elliott (2019) Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists. PhD thesis, University of Nottingham.

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Asthma and chronic obstructive pulmonary disease both involve constriction or obstruction of the airways and are causes of morbidity and mortality worldwide. To treat these conditions, patients are often prescribed β2 adrenoceptor agonists (β2AR). Activation of the β2AR leads to smooth muscle relaxation within the respiratory tract, and therefore increased airflow throughout the lungs. The caveat of current approved drugs, is that due to structural similarities with the β2AR endogenous agonist adrenaline, these compounds can also activate the β1AR. Activation of the β1AR, increases heart rate and force of contraction. This becomes problematic when patients also suffer from heart disease (40% of COPD patients). There is therefore, a requirement for β2AR agonists with efficacy selectivity to the β2AR.

This project aims to develop an efficacy selective β2AR agonist by linking a β2AR agonist pharmacophore, to a selective β1AR antagonist pharmacophore, to form a bivalent compound that will exhibit agonism at the β2AR, but antagonism at the β1AR.

Analogues of the naturally occurring β2AR agonist, S1319, and the highly selective β1AR antagonist CGP 20712A were synthesised and pharmacologically evaluated (performed by the author and Prof. Jillian Baker). Structure-activity relationship studies were performed in an attempt to identify moieties that were β2AR efficacy selective and β1AR affinity selective.

A β2AR agonist group was attached to several β1AR antagonist groups to form a number of bivalent compounds which underwent pharmacological evaluation (performed by Prof Jillian Baker). The results of these studies facilitated the rational design of the efficacy selective β2AR agonist 5.61 which is a partial β2AR agonist– β1AR antagonist.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Stocks, Michael
Baker, Jillian
Scammells, Peter
Keywords: Beta adrenoceptors, pulmonary diseases, COPD, airways,
Subjects: R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 56572
Depositing User: Lumb, Elliott
Date Deposited: 08 Aug 2019 12:23
Last Modified: 22 Jun 2021 04:30

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