SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL NAPHTHALENIC AND BIOISOSTERIC RELATED AMIDIC DERIVATIVES AS MELATONIN RECEPTOR LIGANDS

A series of N-naphthylethyl amide derivatives were synthesized and eva luated as melatonin receptor ligands. The affinity of each compound fo r the melatonin receptor was determined by binding studies using [2-I- 125]iodomelatonin on ovine pars tuberalis membrane homogenates. Struct ure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears th at the affinity is strongly affected by the size of the substituent of the nitrogen of the amidic function. Many of these ligands give bipha sic dose-response curves which suggests that there may be two melatoni n receptor subtypes within the ovine pars tuberalis cells. The replace ment of naphthalene by benzofuran or benzothiophene did not strongly a lter the affinity for the melatonin receptor. In contrast, the benzimi dazole analogue was a poor ligand. Compound 7, the naphthalenic analog ue of melatonin, a selective ligand of the melatonin receptor and an a gonist derivative, has been selected for clinical development.