Vonhoff, Stefan; (1994) Synthesis of conformationally restricted melatonin analogues. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The pineal hormone melatonin plays a major role in the regulation of seasonal cycles and the control of circadian rhythms in mammals, reptiles and birds. The emerging potential of melatonin in the therapy of human rhythm disorders (i.e. SAD and shift-work syndrome) and its application in agriculture (control of reproductive cycles in farm-animals such as sheep and horses) has caused a dramatic upsurge of interest in synthesising melatonin agonists and antagonists. As part of a programme to examine the three-dimensional structure of the melatonin receptor the synthesis and biological activity of several structural melatonin analogues with conformationally restricted N-acyl-3-ethanamine side-chain was investigated. The tricyclic analogue N-butanoyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetra- hydrocarbazole showed the highest affinity in the 2-[125I]-iodomelatonin radioligand binding assay in chick brain membranes (Ki=378 pM, melatonin Ki=580 pM). Displacement of the 6-methoxy moiety effected a change from agonistic to antagonistic properties in the pigment aggregation response test involving melanophores obtained from the neural crest of Xenopus laevis embryos, [beta]-Alkylated melatonin analogues were prepared by Bischler methodology and showed, as well as 4-bromo-melatonin, a retention in binding potency. Several synthetic routes towards N-acyl-nortryptamines, 2-substituted cyclopent[b]- and 9-substituted cyclohept[b]-indoles were investigated. Biological results were evaluated by correlating the binding affinity of the melatonin analogues with the conformation of the side chain, the nature of the N-acylating group, and the spatial distance between the methoxy and amide pharmacophores.

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