Unusual reactivity of [beta]-hydroxy-serotonin, a forgotten serotonin derivative

Serotonin (5-HT) is a well-known biogenic amine which regulates mood, sleep, and is involved in muscle contraction and blood coagulation. Based on an analogy to norepinephrine, a [beta]-hydroxylated derivative of dopamine which has diverse physiological functions, beta-hydroxy-serotonin ([beta]-OH-5-HT) originally encouraged interest as a potential pharmacological agent. Four decades ago, its organic synthesis was attempted. However, due to difficulties with the synthesis and the compound's instability, rigorous identification and characterization of [beta]-OH-5-HT proved evasive. Here, we successfully synthesized [beta]-OH-5-HT from 5-HT using a Pseudomonas enzyme, tryptophan side chain oxidase type I (TSOI), and we determined the structure by 2D-NMR and characterized [beta]-OH-5-HT in detail. The CD spectra showed no optical activity, suggesting a racemic mixture. To separate dl-[beta]-OH-5-HT, we synthesized l-Ala-5-HT and derivatized it into erythro- and threo-l-Ala-[beta]-OH-5-HT with TSOI. Interestingly, both isolated fractions returned to a diastereoisomeric mixture within two hours at pH 5.0. Later, we found that, under acidic conditions, [beta]-OH-5-HT readily reacted with nucleophiles like alcohols or thiols, yielding a variety of dl-[beta]-substituted-5-HT. The unusual properties of [beta]-OH-5-HT might be attributed to the unique nature of a [beta]-hydroxyl group adjacent to an indole ring and amino group. The mechanism for the rapid racemization of [beta]-OH-5-HT is discussed.[PUBLICATION ABSTRACT]