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Structure, function and molecular pharmacology of neurotransmitter receptors-polyamines as key tools and potent neuroprotectants

Objective

- To develop novel, potent and specific analogues of polyamine amides and polymethylene tetraamines containing aromatic units.
- To study the interactions of polyamine amides and polymethylene tetraamines with native and cloned acetylcholine and glutamate receptors
- To develop polyamines and polymethylene tetraamines as neuroprotectants.

The project is designed to develop novel, potent analogues of natural neuroactive amines occurring in wasp and spider toxins; these polyamine amides and polymethylene tetra amines containing aromatic groups are of interest as tools for investigating specific neuroreceptors in the central and peripheral nervous system. More importantly, the compounds are potential neuroprotectants for exploitation by the EU pharmaceutical industry. The project will involve close collaboration between medicinal chemists, pharmacologists, molecular biologists, neuropathologists and biochemists to achieve a set of carefully designed goals. The studies will target nicotinic and muscarinic acetylcholine receptors and ionotropic glutamate receptors, and will employ native receptors, in vivo and in vitro, as well as cloned receptors. Antagonism of these receptors by polyamine amides and polymethylene tetraamines will be optimised using biological evaluation as well as physico-chemical and structural characteristics of the compounds. The latter will involve NMR spectroscopy and molecular modelling. The biological optimisation will include receptor binding characteristics and electrophysiology.

Binding domains for the polyamines will be elucidated using photoaffinity labelling, receptor isolation and purification and peptide sequencing. The potential binding domains will be evaluated using cloned receptors mutated at single or multiple sites. A strong synthetic chemistry programme will underpin the biological investigations and provide a series of systematically designed novel compounds with pharmaceutic potential. Selected polyamine amides and polymethylene tetraamines emanating from these studies will be synthesised in quantity and evaluated in whole animal assays for their neuroprotective properties.

Funding Scheme

CON - Coordination of research actions

Coordinator

University of Nottingham
Address
University Park
NG7 2RD Nottingham
United Kingdom