Abstract
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).
Highlights
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter that modulates a wide range of physiological and behavioral functions of the central nervous system (CNS), including cognition, mood, mating, feeding, and sleeping [1,2,3]. 5-HT receptors are members of the G-protein-coupled receptor superfamily, which are categorized into seven major families, 5-HT1−7
Extensive studies have revealed that the 5-Hydroxytryptamine type 2A (5-HT2A) receptor played a critical role in the regulation of neuropsychiatric disorders associated with depression, Parkinson’s and Alzheimer’s disease [4,5,6,7]
In our continuing program on the discovery of 5-HT2A receptor antagonists from marine bacterial culture broths, the EtOAc extract from Pseudoalteromonas rubra QD1-2 displayed promising activity
Summary
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter that modulates a wide range of physiological and behavioral functions of the central nervous system (CNS), including cognition, mood, mating, feeding, and sleeping [1,2,3]. 5-HT receptors are members of the G-protein-coupled receptor superfamily, which are categorized into seven major families, 5-HT1−7. 5-HT receptors are members of the G-protein-coupled receptor superfamily, which are categorized into seven major families, 5-HT1−7. The 5-HT2 receptor subfamily contains three members, namely 5-HT2A, 5-HT2B, and 5-HT2C. Extensive studies have revealed that the 5-HT2A receptor played a critical role in the regulation of neuropsychiatric disorders associated with depression, Parkinson’s and Alzheimer’s disease [4,5,6,7]. A 5-HT2A receptor antagonist is therapeutically relevant for neurological disorders. M100907 with the 5-HT2A antagonist activity has entered onto the phase II clinical trial for the treatment of schizophrenia [8]. In our continuing program on the discovery of 5-HT2A receptor antagonists from marine bacterial culture broths, the EtOAc extract from Pseudoalteromonas rubra QD1-2 displayed promising activity
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