DESIGN AND SYNTHESIS OF NEW NAPHTHALENIC DERIVATIVES AS LIGANDS FOR 2-[I-125]IODOMELATONIN BINDING-SITES

New melatonin-like agents were designed from the frameworks of 2,5-dim ethoxyphenethylamine, an important structural moiety for the 5-HT rece ptor, and (2-methoxynaphthyl)-ethylamine. The compounds were synthesiz ed by classical methods and evaluated in binding assays with chicken b rain membranes using 2-[I-125]iodomelatonin as the radioligand. Prelim inary studies on the series of N-acyl-disubstituted phenethylamines sh owed 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) fo r N-[2-(2-methoxy-5-bromophenyl)ethyl]propionamide (3o). This effect w as confirmed in a series of the naphthalene derivatives, a bioisosteri c moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-[2-(2-methoxynaphthyl)ethyl]prop ionamide (4b) (K-i = 0.67 +/- 0.05 nM) and -(2,7-dimethoxynaphthyl)eth yl]cyclopropylformamide (K-i = 0.05 +/- 0.004 nM) (4k). Structure-acti vity relationships are discussed with regard to melatonin and bioisost eric naphthalenic compound 2. The K-i value for 4b was affected to a s imilar extent to that of melatonin by GTP-gamma-S or Mn2+ in competiti on experiments, suggesting an agonist profile for this compound.