Davies, David J.; (1999) The synthesis and biological evaluation of several series of melatonin agonists and antagonists. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The work contained in this thesis forms part of an ongoing programme to examine the structure of the melatonin receptor by synthesis of indole based melatonin analogues. The thesis is divided into five chapters. In Chapter One, an overview of the biosynthesis and physiological activity of the pineal hormone melatonin is presented. Receptor structure and distribution are also discussed, followed by a review of analogue studies reported in the literature up to the end of 1998. Chapter Two describes the results of studies aimed at the introduction of an element of conformational restriction to the C3 side chain of melatonin. A series of 1-methylcycloalkan[b]indoles was synthesised which had high affinity in the 2-[125I]-iodomelatonin radioligand binding assay and excellent biological potency in the Xenopus Laevis assay. Several racemic compounds from this series were resolved into enantiomers by chromatography and the melatonin receptor shown, for the first time, to be capable of chiral discrimination. The (R)-(-) enantiomers were demonstrated to be considerably better (up to 130 fold) at binding to the melatonin receptor and up to 400 times more potent than the (S)-(+) enantiomer. Several routes towards 1-H-cycloalkan[b]indoles were investigated. Chapter Three reports the synthesis and results of an exploratory investigation into the potential of Nb-acyltetrahydro-β-carbolines as ligands for the melatonin receptor. No significant new agonists were obtained and many of the compounds showed antagonist behaviour. Chapter Four includes the synthesis of several individual analogues or small sets of compounds aimed at fulfilling a specific requirement. Attempts were made to synthesise some novel analogues by direct substitution reactions on melatonin itself, and some attempts were made to alter postulated hydrogen bonding sites between ligand and receptor by replacing oxygen atoms in the pharmacophores with sulphur. Chapter Five contains the experimental details for Chapters Two to Four.

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