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Novel Functional Domains On Adrenoceptors For Drug Interaction And Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$801,500.00
Summary
Our work involves studying cell-surface proteins (receptors) that respond to hormones such as adrenaline or substances that transmit signals in the nervous system (neurotransmitters). These receptors play a vital role in orchestrating responses to stimuli such as stress, pain, changes in blood pressure, body temperature, fluid and energy status, and exercise. They allow communication between different organs or different parts of the nervous system. G-protein coupled receptors (GPCRs) are the ma ....Our work involves studying cell-surface proteins (receptors) that respond to hormones such as adrenaline or substances that transmit signals in the nervous system (neurotransmitters). These receptors play a vital role in orchestrating responses to stimuli such as stress, pain, changes in blood pressure, body temperature, fluid and energy status, and exercise. They allow communication between different organs or different parts of the nervous system. G-protein coupled receptors (GPCRs) are the major group of cell surface receptors that interact with hormones and neurotransmitters. Treatment of many diseases and conditions relies on the use of drugs that selectively activate or block a single type of GPCR. In fact, about 2-3 of existing therapies are based on these drugs. In designing new drugs it is important to understand as much as possible about the properties of the target receptors. There is emerging evidence concerning interactions between drugs, receptors and proteins inside cells that translate signals into responses (signalling proteins). For example, receptors have additional sites of drug action that can modulate their activity, and can also couple to multiple signalling pathways. We are studying adrenoceptors that respond to adrenaline and to the neurotransmitter noradrenaline. Our studies will use adrenoceptors as model systems to identify novel potential sites for drug interaction, to gain new insights into signalling mechanisms utilized by these receptors and to examine how a variety of phosphorylation mechanisms affect the ability of receptors to couple to particular signalling pathways.Read moreRead less
Molecular Pharmacology Of Beta Adrenoreceptors In Multiple Disease States
Funder
National Health and Medical Research Council
Funding Amount
$578,812.00
Summary
Obesity is a major and increasing health concern for almost half the adult population, and is associated with serious medical conditions including diabetes and heart disease. Changes in behaviour such as increasing physical activity and eating less high-calorie food help many people reduce their body weight, however many others have a genetic predisposition to become overweight and behavioural measures are ineffective. Although anti-obesity drugs should be a valuable adjunct to lifestyle changes ....Obesity is a major and increasing health concern for almost half the adult population, and is associated with serious medical conditions including diabetes and heart disease. Changes in behaviour such as increasing physical activity and eating less high-calorie food help many people reduce their body weight, however many others have a genetic predisposition to become overweight and behavioural measures are ineffective. Although anti-obesity drugs should be a valuable adjunct to lifestyle changes, the currently available appetite suppressants are not ideal. Our work involves studying particular cell-surface proteins (receptors) which normally respond to hormones such as adrenaline. The beta(3)-adrenergic receptor is known to mediate the breakdown of fats and increased heat production in adipose tissue and possibly muscle. Administration of beta(3)-selective drugs to obese mice promotes weight loss and a reduction of diabetic symptoms, and a number of drugs targetting the human beta(3)-adrenergic receptor are being developed by pharmaceutical companies. We are trying to understand more about the properties of this receptor, as this information will assist in designing drugs which are more selective and more potent. Sometimes drugs act at more than one receptor, and there is evidence that this may be the case for two drugs called CGP 12177 and BRL 37344 which stimulate the beta(3)-adrenergic receptor. The second major aim of our project is to find out whether these drugs act at a novel receptor which is related to the beta(3)-adrenergic receptor and also mediates energy expenditure and heat production in adipose tissue and skeletal muscle. The discovery of a new receptor would provide additional scope for the development of effective anti-obesity treatments.Read moreRead less
Molecular Attributes And Physiological Significance Of Beta1L-adrenoceptors
Funder
National Health and Medical Research Council
Funding Amount
$754,353.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure. We have discovered that one group of beta-blockers not only blocks the receptor but stimulates it. To explain this we hypothesize that human beta-adrenoceptors exist in two different 'states' , high and low. We are now determining whether 1. the low state causes progression of heart failure, 2. the molecular basis of the two states and 3. we can make new compounds to block the low state.
Contractile And Relaxant Effects Of B2- And B1-adrenoceptors In Human Heart: Blockade By A Third Generation B-blocker
Funder
National Health and Medical Research Council
Funding Amount
$136,320.00
Summary
The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenocept ....The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenoceptors. When activated, b-adrenoceptors cause an increase in the force of each heart beat and a reduction in the duration of each heart beat. This may be an advantage in conditions where the heart beat is too long. In this study we propose to map the biochemical pathways through which b-adrenoceptors affect each heart beat. The therapeutic management of heart failure has been revolutionized by the use of compounds which block b-adrenoceptors. One such drug, carvedilol is currently used in this country. The way in which it works may not be fully understood. In preliminary experiments we have identified a novel mechanism for carvedilol directly in human heart in which it may work and contribute to it's beneficial effects in the management of heart failure. Our studies will focus on this finding.Read moreRead less
Novel Actions Of Beta-adrenoceptor Antagonists: Implications For The Treatment Of Cardiac Failure
Funder
National Health and Medical Research Council
Funding Amount
$142,630.00
Summary
Almost 2-3 of drugs on the market act on G protein-coupled receptors, and many are antagonists that block receptors. Antagonists were seen as inert compounds that prevent access of natural neurotransmitters or hormones, but recent studies indicate distinct actions. We believe that atypical effects of beta-adrenergic antagonists may explain their usefulness in treating cardiac failure. We seek to understand the process and develop assays to aid the development of new drugs for cardiac failure.