Synthesis of new arylalkoxy amido derivatives as melatoninergic ligands.

Cécile Pégurier, Laurence Morellato, Eminn Chahed, Jean Andrieux, Jean Paul Nicolas, Jean A Boutin, Caroline Bennejean, Philippe Delagrange, Michel Langlois, Monique Mathé-Allainmat

Index: Bioorg. Med. Chem. 11 , 789-800, (2003)

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Abstract

Amido derivatives 10-18 of the corresponding oxyamines were synthesised as melatoninergic ligands by the reaction of hydroxyphtalimide with the halogeno derivatives or the corresponding alcohols using Mitsunobu reaction conditions. The affinity of the compounds for chicken brain melatonin receptors and recombinant human MT(1) and MT(2) receptors was evaluated using 2-[125I]-iodomelatonin as the radioligand. Overall, the introduction of an oxygen atom in the amido chain was not a favourable parameter as the compounds were less potent than the corresponding deoxy derivatives. However, nanomolar compounds were obtained with the arylethyloxy derivatives (13c (R'=nPr), chicken brain, hMT(1), hMT(2), K(i) values: 4.8, 3.86, 2.4 nM, respectively) and the 2,7-dimethoxynaphthalene derivatives (17c (R'=nPr), chicken brain, hMT(1), hMT(2), K(i) values: 0.04, 0.13, 0.1 nM, respectively). The functional activity of these compounds was evaluated by the aggregation of melanophores in Xenopus laevis tadpoles and the potency was related to the affinity of the molecules for melatonin receptors. The compounds were found to be full agonists and compound 17a was 20-fold more potent than melatonin in this bioassay.