Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists
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 relaxa...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2019
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| Online Access: | https://eprints.nottingham.ac.uk/56572/ |
| _version_ | 1848799348599554048 |
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| author | Lumb, Elliott |
| author_facet | Lumb, Elliott |
| author_sort | Lumb, Elliott |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:34:14Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-56572 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:34:14Z |
| publishDate | 2019 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-565722025-02-28T14:29:53Z https://eprints.nottingham.ac.uk/56572/ Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists Lumb, Elliott 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. 2019-07-22 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/56572/1/Elliott%20Lumb%20Thesis%20Final%20.pdf Lumb, Elliott (2019) Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists. PhD thesis, University of Nottingham. Beta adrenoceptors pulmonary diseases COPD airways |
| spellingShingle | Beta adrenoceptors pulmonary diseases COPD airways Lumb, Elliott Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists |
| title | Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists |
| title_full | Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists |
| title_fullStr | Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists |
| title_full_unstemmed | Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists |
| title_short | Design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists |
| title_sort | design, synthesis and pharmacological evaluation of efficacy selective β2 adrenoceptor agonists |
| topic | Beta adrenoceptors pulmonary diseases COPD airways |
| url | https://eprints.nottingham.ac.uk/56572/ |