Synthesis of β-Substituted Naphth-1-yl Ethylamido Derivatives as New Melatoninergic agonists

Naphthalene melatoninergic ligands with alkyl groups (Me, Et, Pr, Bz) in the β position of the ethylamido chain were synthesised. The affinity of the compounds for chicken brain melatonin receptors was evaluated using 2-¹²⁵I]-iodomelatonin as the radioligand. An increase in the affinity was observed with the β-methyl derivatives and the greatest increase was seen with the (−) enantiomers. The introduction of a 2- or 7-MeO group on the naphthalene ring and the lengthening (Et, Pr) of the alkylamido chain gave potent compounds such as (−)1h (K_i=24 pM). The functional activity of these compounds was evaluated by the aggregation of melanophores in Xenopus laevis tadpoles. The potency to produce lightening of the skin of Xenopus laevis was related to the affinities values of the molecules at melatonin chicken brain receptors. The most potent ligands were found to be full agonists and compound 1h was 25 fold more potent than melatonin in this bioassay.