STRUCTURE-ACTIVITY-RELATIONSHIPS FOR SUBSTRATES AND INHIBITORS OF PINEAL 5-HYDROXYTRYPTAMINE-N-ACETYLTRANSFERASE - PRELIMINARY STUDIES

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 t ryptamine (K-m = 0.05 mM), while the substituted naphthalene and pheny l derivatives were less potent. However, the K-m values seem be influe nced 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 stru cture-activity relationship was observed. Melatonin and several bioiso teric derivatives were shown to be inhibitors of 5-HT-N-acetyltransfer ase. Preliminary data suggested that over the 5-50-mu M concentration range, melatonin was a competitive inhibitor (IC50 = 10 mu M) with a c oncentration-dependent inhibitory effect on its own synthesis in the p ineal gland. However, the bioisosteric naphthalene derivatives were ch aracterized instead as mixed inhibitors. (1-Napthyl)ethylacetamido, a putative melatoninergic antagonist, was also shown to be an inhibitor of 5-HT-N-acetyltransferase (IC50 = 8 mu M) and is a promising tool fo r the regulation of melatonin synthesis and the understanding of its r ole.