Discovery and Structure-Based Optimization of 6-Bromotryptamine Derivatives as Potential 5-HT2A Receptor Antagonists.

5-Hydroxytryptamine type 2A (5-HT2A) receptor is an important target for developing innovative antipsychotic agents in neuropsychiatric disorder therapies. To search for 5-HT2A receptor antagonists, a new indole alkaloid termed 6-bromo-N-propionyltryptamine (1), together with one known homologue 6-bromo-N-acetyltryptamine (2) were isolated and identified from a marine bacterium Pseudoalteromonas rubra QD1-2. Compound 1 with an N-propionyl side chain exhibited stronger 5-HT2A receptor antagonist activity than that of N-acetyl derivative (2), indicating that 6-bromotryptamine analogues with a longer chain acyl group perhaps displayed a more potent capacity to the target. Therefore, a series of new 6-bromotryptamine analogues (3-7) with different chain length of the acyl group (C4-C8) were prepared and evaluated activity against 5-HT2A receptor. Remarkably, 6-bromo-N-hexanoyltryptamine (5) displayed the most effective inhibitory activity, which was 5-fold stronger than that of the parent compound 1 and showed 70% efficacy of the positive control (ketanserin tartrate).