Structure-activity relationships for substrates and inhibitors of pineal 5-hydroxytryptamine-N-acetyltransferase: preliminary studies

Abstract Tryptamine, (1-naphthyl)ethylamine and phenethylamine derivatives were tested as substrates of ovine pineal serotonin- N -acetyl transferase (5-HT-NAT), a key enzyme involved in the synthesis of melatonin. Almost all of the indole derivatives possessed affinity similar to that of tryptamine ( K m = 0.05 mM ), while the substituted naphthalene and phenyl derivatives were less potent. However, the K m values seem be influenced by the steric hindrance and polar properties of the substituent. V max values for the naphthyl and phenyl derivatives were generally 10–20-fold higher than those of the indole derivatives and no clear structure-activity relationship was observed. Melatonin and several bioisoteric derivatives were shown to be inhibitors of 5-HT- N -acetyltransferase. Preliminary data suggested that over the 5–50-μM concentration range, melatonin was a competitive inhibitor (IC 50 = 10 μM) with a concentration-dependent inhibitory effect on its own synthesis in the pineal gland. However, the bioisosteric naphthalene derivatives were characterized instead as mixed inhibitors. (1-Napthyl)ethylacetamido, a putative melatoninergic antagonist, was also shown to be an inhibitor of 5-HT- N -acetyltransferase (IC 50 = 8 μM) and is a promising tool for the regulation of melatonin synthesis and the understanding of its role.