Design and Synthesis of New Naphthalenic Derivatives as Ligands for 2-Iodomelatonin Binding Sites

Article abstract of DOI:10.1021/jm00012a004

New melatonin-like agents were designed from the frameworks of 2,5-dimethoxyphenethylamine, an important structural moiety for the 5-HT receptor, and (2-methoxynaphthyl)ethylamine.The compounds were synthesized by classical methods and evaluated in binding assays with chicken brain membranes using 2-(125I>iodomelatonin as the radioligand.Preliminary studies on the series of N-acyl-disubstituted phenethylamines showed the favorable role of the methoxy group in the ortho position of the side chain on the affinity for the receptor ( K_i = 8 +/- 0.2 nM ) for N-<2-(2-methoxy-5-bromophenyl)ethyl>propionamide (3o).This effect was confirmed in a series of the naphthalene derivatives, a bioisosteric moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-<2-(2- methoxynaphthyl)ethyl>propionamide (4b) ( K_i = 0.67 +/- 0.05 nM ) and N-<2-(2,7-dimethoxynaphthyl)ethyl>cyclopropylformamide (K_i = 0.05 +/- 0.004 nM ( (4k).Structure-activity relationships are discussed with regard to melatonin and bioisosteric naphthalenic compound 2.The K_i value for 4b was affected to a similar extent to that of melatonin by GTP-γ-S or Mn²⁺ in competition experiments, suggesting an agonist profile for this compound.