medicinal chemistry & drug discovery


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

Synthetic cannabinoids as "designer drugs"

Synthetic cannabinoids (SCs) are the most rapidly evolving class of widely abused “designer drugs”, and pose a major public health concern. More than 60 SCs of abuse have been identified, with more than 20 new SCs discovered in 2012 alone. In Australia, a recent survey of SC users revealed that more than two-thirds of respondents experienced at least one serious side-effect when using SCs. The most recently identified SCs, such as JWH-018, XLR-11, BB-22, and SDB-001, will be synthesised, along with their metabolites. These targets, allowing the generation of detailed structure-activity profiles for functional selectivity in vitro. Selected compounds will undergo toxicological analysis in vivo, representing the first ever attempt to systematically attribute the toxicity of emergent SCs to differences in CBR activation and non-cannabinoid target interactions.

 

 

 


Project 3

Tau aggregation inhibitors for Alzhiemers disease

Alzheimer's disease (AD) is characterized by tau-protein containing neurofibrillary tangles (NFTs). Normal tau binds to microtubules and facilitates microtubule assembly and stability. However when the balance between tau phosphorylation and dephosphorylation is changed in favour of the former, tau is hyperphosphorylated and the level of the free tau fractions elevated. The hyperphosphorylation of tau protein and formation of NFTs leads to AD pathology. During NFT formation, tau forms a variety of different aggregation species, including tau oligomers, granules, and fibrils. The inhibition or reversal of tau aggregation is a potential therapeutic strategy for the development of disease modifying therapeutics for AD. Recently a quantitative high-throughput screening (qHTS) of ∼300 000 compounds was conducted and several aminothienopyridazines (ATPZs) were identified as novel, drug-like inhibitors of tau aggregation. The current project will utilise the depicted ATPZ as a lead structure, with a deconstruction-reconstruction-elaboration approach used to generate new preclinical candidates with potency, selectivity and blood-brain barrier penetration.

 

 


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:

Professor Michael Kassiou

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/