drug discovery & medicinal chemistry
The field of medicinal chemistry is a key component in the drug discovery process. Research in the Kassiou group utilizes modern organic chemistry techniques for the rational design and synthesis of novel compounds for a range of CNS targets which are associated with neuropathologies such as schizophrenia, Alzheimer’s disease, Parkinson’s disease, anxiety and depression. The projects below are only a sample of what is offered, and projects can be tailored to suit the specific interests of any student.
Project 1
Small molecule oxytocin receptor agonists
It has been previously suggested that oxytocin may act as a natural antipsychotic. Oxytocin administration in humans is currently under trial for the treatment of many psychiatric disorders with recent success in autism and social anxiety disorder. Although there is no crystal structure of the oxytocin receptor, the identification of a possible ligand interaction pocket has resulted in a proposed oxytocin binding site. The need for small molecule agonists that mimic the activity of this cyclic nonapeptide hormone has resulted in the discovery of a pyrazole-fused benzodiazepine. We will elaborate the structure-activity relationships of this molecule and use this information to design new oxytocin receptor agonists as potential therapeutic agents.
Project 2
Nicotinic ligands for the treatment of Alzheimer's disease
Nicotinic acetylcholine receptors (nAChRs) play an important role in complex brain functions, and in the pathogenesis of several brain disorders, such as Alzheimer’s disease. There are at least 2 acetylcholine (ACh) binding sites on the major brain nAChR subtype. The design and synthesise of novel ligands containing 2 pharmacophoric units will allow interaction at both sites on this receptor simultaneously.
It is anticipated that these bivalent ligands will bind with co-operativity to enhance ligand affinity and nAChR subtype selectivity. These improved binding characteristics will be important for the development of effective therapeutics.
Project 3
Polycyclic compounds in depression and schizophrenia
Polycyclic molecules offer medicinal chemists a rigid framework for the development of new pharmaceuticals. In these projects, structure-activity relationships (SAR) will be generated for several series of polycyclic-based molecules. These new molecular entities will be designed to target purinergic P2X7 and sigma receptors for applications in depression and schizophrenia, respectively. Newly synthesised compounds will be screened “in house” using cell based assays and in vivo animal behavioural studies.
Project 4
Azaspirocycles as piperazine bioisosteres targeting sigma receptors
Piperazine is one of the most widely occuring heterocycles in medicinal chemistry. This fact has inspired the investigation of new chemical entities capable of acting as piperazine bioisosteres, such as azaspirocycles. Drug discovery efforts within our group have produced piperazine 1, a highly selective, picomolar sigma receptor ligand. Efforts have been directed towards the development of selective agents targeting sigma receptors as potential anxiolytics, antidepressants, and neuroprotective agents with novel modes of action. Compound 1 has been labelled with fluorine-18, allowing high resolution imaging of sigma receptors in a living baboon using positron emission tomography.
The synthesis of conformationally-restricted azaspirocyclic analogues of 1 aims to improve the in vivo pharmacokinetic profile of this class of sigma ligands. A library of structures, including spiroazetidines 2 and 3, will be generated from the boxed synthetic building blocks shown in the scheme below.
For further information, please contact:
Room 516
School of Chemistry
Eastern Avenue
University of Sydney NSW 2006
Phone: +61 2 9351 2745
Email: michael.kassiou@sydney.edu.au
Website: http://sydney.edu.au/science/chemistry/~kassiou/