N-acyl-3-amino-5-methoxychromans: a new series of non-indolic melatonin analogues.

A novel series of melatonin analogues is described which are based on the chroman nucleus. These N-acyl-3-amino-5-methoxychromans competitively inhibit [125I]2-iodomelatonin binding to chicken brain membranes although with reduced affinity compared to melatonin. The slope of the competition curves suggests the interaction of the chromans with a single binding site. On cultured Xenopus laevis melanophores, the chroman analogues produce different responses; N-chloroacetyl-3-amino-5-methoxychroman (ClaMCh), like melatonin, is a full agonist at the melanophore receptor and produces a complete aggregation of pigment granules. In contrast, N-acetyl- and N-cyclopropyl-3-amino-5-methoxychroman have no agonist activity, while N-propionyl- and N-butanoyl-3-amino-5-methoxychroman produce only partial aggregation of pigment. ClaMCh is 40-fold weaker at inducing pigment aggregation in melanophores (EC50 = 15 microM) than in inhibiting [125I]2-iodomelatonin binding in chicken brain membranes (Ki = 0.38 microM) suggesting that this analogue may discriminate between melanophore and chicken brain melatonin receptors. Chroman-based melatonin analogues may be useful tools for characterizing potential melatonin receptor subtypes.