Development of Positive Allosteric Modulators of P2X4 for the Treatment of Multiple Sclerosis

Development of Positive Allosteric Modulators of P2X4 for the Treatment of Multiple Sclerosis

The Project

Multiple sclerosis (MS) affects millions of people world-wide. Currently there are no effective methods for slowing the progression of MS. Having identified compounds that act on an ion channel implicated in slowing the progression of MS, analogues of these hits will be investigated to ultimately develop a novel therapeutic. This is a joint project between Dr Honey at the University of Greenwich (chemistry lead) and the Sussex Drug Discovery Centre at the University of Sussex (biology lead).

Expected Outcomes and Goals

Although agonists of P2X4 exist, they mostly consist of analogues of the native ligand ATP, and so are acting as non-selective competitive binders – therefore the development of a selective agonist is needed. During a previous screening campaign for antagonists of P2X4, two chemically distinct compounds exhibited the desired selective agonist behaviour compared to the relative response of ATP (the natural ligand). SAR investigations will be conducted using single point changes, probing each functional group in order to investigate its role within the pharmacophore. The goals of this project are to further investigate the pharmacology/physiology of P2X4 agonism, with the aim of developing a novel therapeutic to treat multiple sclerosis. Publication of the findings will be through peer-reviewed journals, patents and disseminated through posters/talks at online or face-to-face conferences.

The Candidate

The project is suitable for a student with a strong and keen interest in synthetic organic chemistry, and medicinal chemistry/drug discovery.

The Laboratory and Department

The group and department are well equipped with state-of-the-art instruments such as automated purification, glove box, 4 x NMR spectrometers, UPLC-MS, high-resolution mass spectrometer, MALDI-TOF, etc

Synthesis of Oxetanes from Flow-Generated Isocyanides

The Project

The need for novel methodologies to access heterocyclic compounds is not new; the abundance of these compounds in nature, as well as their utility in medicinal chemistry, materials chemistry, agricultural chemistry etc. has spurred new and improved ways to access these compounds. Methodology that has inbuilt points of diversity to synthesise different heterocycles – the changing of one reactant enabling the synthesis of multiple heterocyclic systems - is hugely powerful.

With the above in mind, this project aims to develop novel methodology for the synthesis of oxetanes (and subsequently a range of heterocyclic compounds) from flow-generated isocyanides as a common precursor.

Expected Outcomes and Goals

The expected outcomes and goals for this project are as follows: methodology will be established for the synthesis of isocyanides in the fReactor™ and their subsequent use in a novel synthesis of oxetanes and subsequent heterocyclic compounds. Publication of the findings will be through peer-reviewed journals and disseminated through posters/talks at online or face-to-face conferences.

The Candidate

The project is suitable for a student with a strong and keen interest in synthetic organic chemistry.

The Laboratory and Department

The group and department are well equipped with state-of-the-art instruments such as automated purification, glove box, 4 x NMR spectrometers, UPLC-MS, high-resolution mass spectrometer, MALDI-TOF, etc