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Design and development of melatonin analogues as putative chronobiotics

Jones, Robert M.; (1995) Design and development of melatonin analogues as putative chronobiotics. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The indoleamine melatonin [N-acetyl-5-methoxytryptamine] 1 is a neurohormone synthesised and secreted by the vertebrate pineal gland on a circadian basis (circa meaning about and dies meaning day) with elevated peripheral blood levels being attained at night. The interest in the sites and mechanism of action of this endogenous indole has been steadily growing since it was first isolated and synthesised by Lerner and co-workers in 1958. [diagram]. Me-Ov N H 1 In vertebrates, the primary sites of production of this hormone are the pinealocytic cells of the pineal gland and the photoreceptor cells of the retina. Both tissues synthesise melatonin from serotonin via a two step biochemical pathway. Melatonin is known to play a key role in the transduction of photoperiodic information by acting as an endogenous zeitgeber. It acts to translate photoperiodic information from the environment with the circadian melatonin signal being de-coded by high affinity binding sites in the CNS. Through this mechanism 1 plays a fundamental role in modulating a variety of endocrinological, neurophysiological and behavioural functions, including the regulation of reproduction in most mammals living in the temperate zones, the control of circadian rhythms in reptiles, birds and mammals and it alters certain aspects of retinal physiology such as photoreceptor retinomotor movements and photoreceptor outer segment disc shedding. The exact role of 1 in humans is less explicit, but recent research has clearly demonstrated the presence of melatonin receptors in the human circadian clock as well as the ability of humans to respond to the melatonin signal with a well defined circadian phase response curve. Changes in the melatonin rhythm and peripheral blood levels are now thought to be implicated in a number of pathological and physiological conditions, such as seasonal affective disorder (SAD), regulation of sleep-wake cycles, delayed sleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS), puberty, jet-lag, reproduction and shift work disturbances. Melatonin is also reported to have an oncostatic action and modulate the immune response. The relatively recent discovery that 2-[125I|]-iodomelatonin is a high affinity radioligand agonist has led to the development of a number of quantitative in vitro receptor bioassays that have allowed pharmacological characterisation of the melatonin receptor. Tools such as 2-[125I]-iodomelatonin have enabled researchers to begin to develop potent melatonin agonists and some antagonists as chronobiotics. A chronobiotic is defined as a chemical substance capable of therapeutically re-entraining short term dissociated or long term desynchronised circadian rhythms or prophylactically preventing their disruption following environmental insult. Despite the practical and clinical interest in melatonin, very little is actually known about its mode of action nor the way in which it interacts with its receptor. High affinity binding sites have been identified in the central and, more recently, in peripheral tissues, and very recently the Xenopus laevis melanophore receptor, a sheep and a human receptor have been cloned. Advantage can now be taken of these advances in our knowledge of the receptor characteristics and structure to attempt to model the binding of 1 to its receptor and to use this model to design potent chronobiotics. The current work attempts to address this question and provides detailed descriptions of the synthesis and biological evaluation of several new series of chronobiotics. The Heward and Hadley hypothesis that the C5-methoxyl group governs intrinsic activity has been re-examined and a number of compounds bearing C2 substituents and with N-acyl variations, but all lacking C5-methoxyl functionality have been developed that refute this theory about the structural determinants required for melatoninergic activity. An extensive examination of the effects of 2-phenyl substitution of the indole nucleus is also reported, both in terms of binding against 2-[125I]-iodomelatonin in chick brain homogenates and in two in vitro functional assay systems. This study has furnished some of the most potent melatonin agonists reported to date, such as N-[2-(5-methoxy-2-phenyl-1H-indol-3-yl)ethyl]-trifluoroacetamide (283) (Ki chick brain=19 pM, Melatonin Ki chick brain=508 pM). Analogues bearing β-substituents on the tryptamine side arm are reported, as are compounds with variations at the C5 position within this C2-Ph series. Preliminary studies on the synthesis and evaluation of a novel series of isoindolo[2,1a]indole systems is also documented. Biological evaluation of some of these drugs in different in vitro assays putatively suggests heterogeneity of melatonin receptors in two different species. Acting in the nanomolar range some of these compounds are the most potent melatonin antagonists yet discovered and their structural features suggest modifications that might increase binding affinity whilst retaining their antagonistic activity.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Design and development of melatonin analogues as putative chronobiotics
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Melatonin
URI: https://discovery.ucl.ac.uk/id/eprint/10104830
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