Isabelle Charton

Substituted oxygenated heterocycles and thio-analogues : Synthesis and biological evaluation as melatonin ligands

A new series of substituted oxygenated heterocycles and thio-analogues were synthesized and evaluated as melatonin receptor ligands. The replacement of the indolic moiety of melatonin by heterocyclic skeleton such as 1,4-benzodioxin, 2,3-dihydro-1,4-benzodioxin, chroman, 2,3-dihydro-1,4-benzoxathiin, thiochroman, carrying the amidic chain on the aromatic ring, leads to compounds showing a weak affinity for melatonin receptors, except for the compounds 1cb and 1hb.

Synthesis and Biological Activity of New Melatonin Receptor Ligands

To discover analogues of melatonin with a longer half-life, novel non-indole analogues of the compound, in which the amide group of the side-chain has been reversed, have been prepared and evaluated in binding assays to determine their activity on melatonin receptors. The two most active compounds were those with the N-methylbutyramide side-chain. Butyramide and pentanoylamide side-chains resulted in similar affinities, irrespective of the skeleton tested whereas a propionamide side-chain led to loss of affinity. The biological actity of the molecules was more influenced by the length of the side-chain than by the nature of the skeleton, which had little effect. The results obtained show the relative importance of the length of the side-chain and of the nature of the skeleton in both the binding to and the activity on the melatonin receptor of the retroamide series.

Synthesis of 5-substituted-2,3-dihydro-1,4-benzoxathiins: biological evaluation as melatonin receptors ligands.

The synthesis of benzoxathiins bearing a retroamide function is described from 8-hydroxythiochroman, the key step involving the synthesis of the benzoxathiin ring through a sulfonium salt. These new melatonin analogues were evaluated on human receptors MT1 and MT2 and have a similar affinity to that of melatonin itself.