D'Oyley, JM; (2014) Synthesis of Five-Membered Heterocycles: Novel Allosteric Modulators for Nicotinic Receptors and New Gold-Catalysed Reactions. Doctoral thesis , UCL (University College London).

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Abstract

The Drug Discovery project is centred on the design, synthesis and characterisation of novel positive allosteric modulators (PAMs) for α7 nicotinic receptors (nAChR). These receptors are widely found in the central and peripheral nervous systems and are involved in a range of physiological processes. They are active targets for the treatment of pain as well as psychiatric and neurodegenerative disorders. Nicotinic receptors are ion channels which open and allow ions to flow in or out of the neuron upon binding of an agonist. Positive allosteric modulators (PAM) enhance the receptor’s response to the binding of the endogenous agonist, giving greater ion flow than the effect for binding of the agonist alone. A number of novel heterocycles were designed and synthesised and their effect on the α7 nAChR evaluated. The nitrogen heterocycles gave varied pharmacological effects on the receptor and small changes in structure led to large changes in pharmacological activity. During the course of this project we have discovered Au-catalysed and non-catalysed processes for the dihalohydration of alkynols to form diiodoketoalcohols, dichloroketoalcohols and dichlorolactols.

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