Design and synthesis of new heterocyclic and carbocyclic compounds with melatoninergic activity

In the context of this PhD thesis, the synthesis of a series of fused aromatic carbocyclic and heterocyclic melatoninergic compounds has been undertaken.In the introductory chapter, an account of the endocrinological role of the hormone melatonin in mammals, followed by its therapeutic uses in man, is given. Next, a description of the receptors of melatonin is presented and some of the most interesting published melatoninergics are quoted. The introduction is concluded by a brief albeit detailed description of the aims of the present thesis and the design of the new compounds.In the subsequent chapter, a thorough description of the synthetic routes followed for the preparation of the new molecules, is given. The new melatoninergics belong to various chemical classes, which involve the conformationally constrained indole analogues 5 and 6, the tetracyclic compounds II, 12, 13 and 17, their analogues 25-27, 31, 32, 46-48, 53-55 and 39-41 and 65. Apart from these series, new cyclobuta- and cycloheptarenes, compounds 69-71, 77-79, 81-83, 87-89 and 102-104, 114-116, respectively were also prepared. The synthetic part of this chapter is concluded with the methods of preparation of the benzocycloheptenes 96-98 and 111-113.The new molecules were tested for their pharmacological activity, using the well-established Xenopus laevis pigment aggregation model. The indole analogues 5 and 6 are melatonin receptor agonists, with an affinity higher than that of melatonin. The tetracyclic compounds 12 and 13 are melatonin receptor agonists, whilst their gem-dimethyl side chain substituted congeners, II and 17, are partial agonists. Their analogues 25-27, 31, 32, 46-48, exhibit variable melatonin receptor activity ranging from pure agonistic (25-27) to pure antagonistic 31, 32, 46-48 and 53-55. Conversely, their congeners 39-41 and 65 are all pure antagonists. The action of the cyclobutarenes 69-71, 77-79, 81-83, 87-89 varies in accordance with the number of MeO substituents on the benzene nucleus and/or the length of the R group in the side chain. Thus, all the R2 (77-79) and R3 (81-83) monomethoxylated analogues are agonists. Conversely, with the exception of compound 69, their R1 monomethoxylated congeners 70 and 71 are partial agonists. The bis-methoxylated cyclobutarenes 88 and 89 are melatonin receptor agonists, whereas their counterpart 87 (R=Me) is a partialagonist. The cycloheptarenes 102-104 and 114-116 are all antagonists in the Xenopus model, whereas their benzocycloheptene congeners are either pure agonists (96-98) or pure antagonists (compounds 111-113).All new compounds possess stereoelectronic features, which enable them to act as agonist-partial agonist-antagonist molecular probe ―switches‖. An extension of the present thesis could involve the enantioselective synthesis of the most active racemic cyclobuta- and cycloheptarenes