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Title: Targeting neurotransmitter receptors for central nervous system therapeutics : from molecular signalling to behavioural pharmacology
Author: Newman-Tancredi, Adrian
ISNI:       0000 0004 2737 2656
Awarding Body: University of Kent
Current Institution: University of Kent
Date of Award: 2012
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Although chemically-mediated neuronal signaling was discovered nearly a century ago, it was only relatively recently, in the 1980s, that the study of neurotransmitter receptor pharmacology markedly accelerated, with the widespread use of specific radiotracers capable of labelling receptors in tissue preparations. This led to the discovery of an amazing (at the time) diversity of receptor subtypes with distinct physiological properties and pharmacological profiles. Among the principal neurotransmitter receptors to be investigated were those of the monoamines: serotonin (5-hydroxytryptamine, 5-HT), dopamine and noradrenaline, which act at a combined total of at least 27 receptors. The focus of the present D.Sc. thesis is to review the contribution of my own research to the understanding of the molecular signalling, neurochemistry and behavioural pharmacology of central nervous system monoamine receptors. A somewhat unusual feature of this work is that it was mostly carried out in pharmaceutical industry laboratories. These had the enlightened view that creative (and marketable) applied science requires a commitment to innovative basic science. My work therefore combined exploration of previously-unsuspected mechanisms of receptor function with the identification and characterisation of new drugs for use as exploratory tools and/or as therapeutic candidates. The principal advances made in the course of my work were as follows. • Serotonin 5-HT1A receptor signalling: the in vitro studies I conducted revealed the presence of constitutive activity in both recombinant cell lines and native rat brain tissue. The level of G-protein activation by 5-HT1A receptors varies with receptor expression, receptor:G-protein stoichiometry and interactions at specific G-protein subtypes. • 5-HT1A receptor subpopulations: I demonstrated the presence of "biased agonism" at 5-HT1A receptors in specific brain regions. This translated to distinct neurochemical, behavioural and therapeutic-like responses. My work led to the identification of a new selective agonist, F15599, which exhibits reinforced anti-depressant-like activity and was taken to early clinical trials. • 5-HT1A receptor activation in psychotic disorders: the pharmacological studies that I directed showed that compounds possessing 5-HT1A agonist properties exhibit a superior profile of action in models of negative symptoms and cognitive deficits compared with conventional antipsychotics. My work led to the identification of novel drugs, notably F15063. • 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B and 5-HT2C receptors: my research showed that these receptors exhibit diverse profiles of G-protein coupling, biased agonism and constitutive activity. Notably, 5-HT1B receptors exhibited "protean" agonism for the endogenous neurotransmitter, 5-HT. • Dopamine D2, D3 and D4 receptors: these displayed specific molecular signalling mechanisms. D4 receptors showed complex signalling and "promiscuous" activation by noradrenaline, in addition to dopamine. My studies contributed to the identification of novel ligands at D3 and D4 receptors. Of these, S33138, a D3 receptor antagonist, was later tested in schizophrenia patients. • Noradrenergic α2 receptors: I conducted the first multiparametric study of anti-Parkinson's disease agents with differing profiles of action at α2 and other monoamine receptors. The clinical drug, piribedil, was shown to possess α2 receptor antagonism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (D.Sc.) Qualification Level: Doctoral
Keywords: RC321 Neuroscience. Biological psychiatry. Neuropsychiatry ; RM Therapeutics. Pharmacology