Pharmacology

Head of Discipline
Associate Professor Ian Spence
Location
Room 307, Blackburn Building, The University of Sydney

The Discipline of Pharmacology of the University of Sydney is the largest Discipline of its kind in Australia, with an extensive range of research programs and well equipped undergraduate teaching facilities.

The Discipline is well equipped for research and teaching with good facilities for isolated tissue work, tissue culture, behavioural investigations, biochemical, cardiovascular, electrophysiological, molecular biological, radioligand binding, neurochemical and synthetic chemical studies, together with mechanical and electrical workshops.

Major items of equipment include atomic absorption, fluorescence, infrared, nuclear magnetic and ultraviolet spectrometers, gas chromatograph-mass spectrometer, high performance liquid chromatographs and beta radiation counters.

There are on-line computers for anatomical, autradiographical, behavioural, cardiovascular and electrophysiological measurements, a colour graphics system for computer assisted drug design and facilities for data and word processing and slide-making.

GABA Receptors and Transporters
Professor Graham Johnston and colleagues carry out research directed towards the development of drugs selectively active at different types of GABA receptors, transporters and related membrane proteins, using structure-activity studies and computer-assisted modelling. Activity studies are carried out on specific receptors and transporters expressed in oocytes and in other test systems.
Such studies suggest new compounds to be investigated as neuroactive substances, possibly as agonists, antagonists or modulators at these receptors and transporters.

Alzheimer's disease, anxiety, diabetes, epilepsy and schizophrenia are the main targets of our drug discovery program. Major projects include:

• Investigations on the medicinal chemistry, molecular biology and pharmacology of a new class of GABA receptors discovered in the Discipline
• Studies on how GABA receptors are influence by stress
• The development of drugs to treat memory deficits in disorders such as Alzheimer's disease and schizophrenia is being studied under a research and development contract from Polychip Pharmaceuticals, a wholly owned subsidiary of Circadian Technologies Ltd
• Polychip Pharmaceuticals is also supporting investigations on the mechanism of action of some novel modulators of ATP-gated potassium channels directed at discovering new therapeutic agents for the treatment of non-insulin dependent diabetes mellitus
• Assessment of the effects of chemicals in the diet on GABA receptors and transporters, e.g. flavinoids found in soy products, red wine and green tea
• Studies on the molecular biology and pharmacology of the GABA transporters GAT-1 and GAT-2 and
• Investigations on the possible role of GABA receptors in a collaborative project with NISAD, The Neuroscience Institute for Schizophrenia and Allied Disorders

Medicinal Chemistry
Medicinal chemistry studies are carried out by Dr Robin Allan and researchers working in the Adrien Albert Laboratory of Medicinal Chemistry, which is named after Adrien Albert, who established medicinal chemistry in Australia and was the author of many important books, including Selective Toxicity. Much of the work of the group is directed towards the synthesis of heterocyclic compounds that mimic the natural neurotransmitter substances, GABA and glutamate. Pyridazine heterocycles have been identified as particularly interesting compounds. Both synthetic and structure-activity studies are directed towards the discovery of new selective agents that interact with amino acid receptors in the brain, particularly with GABA receptors and the AMPA subtype of glutamate receptors. One of the important features of the work of this research group is that the compounds can be designed, synthesised and tested in isolated tissue preparations.

A further project is part of a wider research effort to develop methods for assaying residual levels of insect growth regulators by immunoassay techniques. The research involves investigation of methods to couple benzoylphenylurea insect control agents to protein, so that the protein conjugates can be used for the induction of specific antibodies.

Molecular Pharmacology of Neurotransmitter Transporters
Dr Robert Vandenberg is investigating the molecular pharmacology of neurotransmitter transporters in the central nervous system. The research group uses a combination of molecular biological and electrophysiological techniques to investigate the molecular basis for the action of endogenous modulators and also novel drugs acting on neurotransmitter transporters.

Glutamate is the predominant excitatory neurotransmitter in the brain and dysfunction of glutamate transporters has been implicated in the pathogenesis of neurological disorders such as motor neurone disease, epilpesy and also ischaemia following a stroke. Our work focuses on understanding the basic mechanisms of transport and how this may influence neurotransmission in normal and pathological situations.

Glycine is both an inhibitory and excitatory neurotransmitter and we are investigating the role of glycine transporters in controlling glycine concentrations in the CNS. Glycine transporters may be useful targets for novel antipsychotic drugs and through a collaborative project with Allelix Neuroscience Inc., we are investigating the mechanism of action of novel glycine transport inhibitors used to treat schizophrenia. This work will provide a better understanding of the potential for manipulation of glycine concentrations as a way treating this debilitating neurological disorder.

Respiratory Pharmacology
Two liaising groups, based in the Discipline of Pharmacology and the Discipline of Pharmacy, constitute the Respiratory Research Group, whose primary interest is the pharmacology and pathophysiology of asthma.

(i) Professor Judith Black and Associate Professor Carol Armour (Discipline of Pharmacy) are funded by the NHMRC and the Asthma Foundation of N.S.W. to investigate the mechanisms of airway hyperresponsiveness, a characteristic feature of asthma. In vitro studies of human lung tissue are necessary because studies in animal tissues are difficult to extrapolate to human asthma. The laboratory has established one of the largest collection facilities for human lung tissue in the world, against a background of collaboration and goodwill from physicians, surgeons, pathologists and transplant co-ordinators. This ready availability of human lung tissue for reactivity studies and human airway smooth muscle primary culture positions the group to address pivotal questions about the underlying pathophysiological events in asthma. Techniques used include primary cell culture, autoradiography, radioligand binding, immunohistochemistry, protein phosphorylation and gel electrophoresis and, in collaborative projects, differential display, gel shift assays and transfection with adenoviral vectors.

In addition, immunopharmacological techniques are used to define abnormalities in inflammatory cell activity. Current projects include the relationship between in vivo and in vitro airway reactivity, IgE and allergic mechanisms in asthma, stimulation and inhibition of human airway smooth muscle cell proliferation, intracellular calcium signalling in contraction and relaxation, passive sensitisation as an in vitro model of asthma, the role of the peptide endothelin, the mechanisms of protein kinase C in airway disease, and the actions of mast cell cytokines and viruses on human airway smooth muscle.

(ii) Professor J Paul Seale is interested in the basic and clinical pharmacology of long-acting adrenoceptor agonists and the potential for the development of tachyphylaxis with these agents or with regular use of conventional agonists in high doses.
A collaborative project with Professor Ken Brown in the Discipline of Pharmacy and Dr Rebecca Mason in the Discipline of Physiology is investigating the systemic bioavailability and potency ratios of inhaled corticosteroids. The potency of esters of inhaled corticosteroids on cytokine production in vitro is being investigated in collaboration with Associate Professor Carol Armour and Dr Margaret Hughes in the Discipline of Pharmacy. Other projects include the role of neuropeptides in psoriasis and the possible peripheral mechanisms for opiate relief of dyspnoea.

Cardiovascular Research
Associate Professor Rosemarie Einstein is conducting research into the changes in cardiovascular receptors which are associated with the development of heart failure. An animal model of heart failure is used, which has many similarities to that which occurs clinically in humans, including a marked reduction in adrenoceptor responsiveness.

The actions of drugs used in the treatment of heart failure are investigated.

Cardiovascular changes in shock, and their effect on the ability of the liver to metabolise drugs (particularly alcohol) are being studied.

The factors which affect ventricular fibrillation and defibrillation thresholds are being investigated, particularly those treatments which may improve the chances of successful defibrillation.

Responses to Laboratory Stresses
The effects of laboratory stresses (including surgical procedures, injections and various housing conditions) are being evaluated in mice. Heart rate and movement are measured telemetrically in conscious, unrestrained mice. The results are correlated with those obtained in isolated tissues taken from the animals post mortem.

Drug and Alcohol Research
Associate Professor Graham Starmer uses driving-related psychomotor performance tests and an instrumented vehicle to evaluate the role of drugs in traffic accidents. Current research is directed towards the feasibility of saliva sampling for detection (by tandem mass spectrometry) of drugs which appear to increase culpability in traffic crashes and the results of a survey in which saliva samples were obtained from uncompromised car, bus and truck drivers are being analysed. Similar analytical techniques have been used to survey drug use by patients admitted to Rozelle Hospital and by a population of chronic schizophrenic patients. Attention has also been directed towards the effects of fatigue on psychomotor performance and the interaction of fatigue with common drugs, such as alcohol and caffeine. Methods to genetically type the enzymes responsible for alcohol metabolism (alcohol dehydrogenase and aldehyde dehydrogenase) have been developed. The acute behavioural effects of alcohol on Asian subjects in nine different sub-groups are being studied, with a view to correlating response (especially skin flushing) with genotype.

Neurotransmitters, Neuromodulators and Hypoxia
Dr Hilary Lloyd is investigating the mechanisms underlying the release of glutamate and aspartate during oxygen and glucose deprivation (in vitro ischaemia), and the effect of a variety of neuroprotectants, including the endogenous neuroprotectant adenosine, on this. Other areas of research are: protein phosphorylation and neurotransmitter release (collaborative study with the Neuroscience Group, University of Newcastle); adenosine and inflammatory mediator release (collaborative study with the Centre for Immunology, St Vincent's Hospital, Sydney); adenosine and apoptosis (collaborative study with the Children's Leukaemia and Cancer Research Centre, Sydney) and dopamine release in the nigrostriatal and mesolimbic systems (with Associate Professor Ewan Mylecharane).

5-Hydroxytryptamine Research
Associate Professor Ewan Mylecharane is investigating the underlying receptor mechanisms involved in some of the actions of 5-hydroxytryptamine (5-HT). Current research is aimed at characterising the receptor mechanisms involved in the actions of 5-HT in blood vessels and in other smooth muscle tissues, as well as its modulating effect on dopaminergic function in the mesolimbic system, using both in vivo and in vitro animal experimental models for functional studies. These investigations are of particular relevance to the development of novel therapeutic agents in disorders such as migraine, carcinoid syndrome, peripheral vascular diseases, schizophrenia and drug abuse.

Pharmacoinformatics: the Application of Artificial Intelligence to Drug Design and Data Analysis
Dr Ian Spence uses soft computing techniques including artificial neural networks, genetic algorithms fuzzy logic and other computational techniques in the design of drugs and the analysis of receptor structure. He is also developing applications of these techniques to other areas of pharmacology, for example, pharmacokinetics and in the analysis of epidemiological data. Current projects include neural net modelling of flexible receptor sites for AIDS drugs, application of cellular automata to the epidemiology of malaria and the application of artificial neural networks to improving artificial reproductive techniques.

Clinical Pharmacology / Drugs and the Elderly
At Royal North Shore Hospital, Clinical Professor Gillian Shenfield and colleagues carry out research projects in a number of areas, including community studies to assess prescribing for the elderly and to investigate doctors' knowledge of medications taken by their elderly patients. Studies have been completed on the use of herbal and other alternative therapies and consumer product information. Current areas of interest are adverse drug reactions in hospital in-patients, the management of elderly patients with atrial fibrillation and evaluating the use of prescribing guidelines.

Hepatic Drug Metabolism
Dr Christopher Liddle leads a research team in the Department of Clinical Pharmacology at Westmead Hospital. The aim of their research is to discern the predominant regulatory factors for a superfamily of enzymes, known as cytochrome P450, found in the human liver. These enzymes form the main route of elimination of many drugs and environmental toxins from the body. Work performed to date, using human liver cells in culture, suggests that hormones may be important in this regulation. Ongoing work aims to elucidate the mechanisms of this regulation at the genetic level. The team works in close collaboration with Professor GC Farrell, as part of the Storr Liver Unit at Westmead Hospital.

Associate Professor Ian Spence
Head of Discipline

Room 307, Blackburn Building, D06
The University of Sydney
NSW 2006 Australia

Phone: +61 2 9351 6954
Fax: +61 2 9351 4717
E-mail: