Summary:
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 partial
