Towards the development of a new class of blockers: design, synthesis and testing of antagonists (blockers) of the low affinity site of the adrenoceptor

Overview

Topic status: We're looking for students to study this topic.

�����blockers are an important class of drugs that are used for the therapeutic management of hypertension, heart failure and other diseases. In heart failure some �����blockers produce a survival benefit. Despite the use of �����blockers the prognosis for heart failure is poor.

There are two binding sites which cause activation of the ��1���adrenoceptor, ��1H and ��1L corresponding to high and low affinity binding sites respectively. All clinically used �����blockers are designed to block ��1H. Recently we have shown that the other site, ��1Luses progression of heart failure. Blockade of ��1L in addition to ��1H may be beneficial for the management of human heart failure.

Hypothesis: �����Blockers that block both ��1L and ��1H-adrenceptors may provide a clinical advantage over currently available ��-blockers for the management of heart failure.

Aims

  • To use molecular modelling to design compounds that specifically block ��1L-adrenceptors
  • To synthesize compounds designed to block ��1L-adrenceptors
  • To test the ability of compounds to block ��1L-adrenceptors

Approaches: A library of compounds has been proposed that will bind to ��1L-adrenceptors and will be the starting point for this project. Molecular modelling will be carried out to optimize compounds prior to synthesis. Selected compounds will be synthesized using standard procedures. Newly synthesized compounds will be assessed for antagonist activity at human ��1L and ��1H-adrenceptors 1. in right atrium obtained from patients undergoing coronary artery bypass surgery and 2. expressed in CHO cells.

This project is the first to specifically design and test compounds that block ��1L-adrenoceptors. It is hoped these experiments will lead to the development of a new class of compounds that more effectively block ��-adrenoceptors in human heart.

Further Reading: Kaumann and Molenaar 2008 Pharmacology and Therapeutics 118, 303-336 The low-affinity site of the ��1-adrenoceptor and its relevance to cardiovascular pharmacology

Study level
Honours
Supervisors
QUT
Organisational unit

Science and Engineering Faculty

Research area

Chemistry

Contact

Please contact the supervisor.