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Unusual reactivity of β-hydroxy-serotonin, a forgotten serotonin derivative

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Abstract

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 β-hydroxylated derivative of dopamine which has diverse physiological functions, beta-hydroxy-serotonin (β-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 β-OH-5-HT proved evasive. Here, we successfully synthesized β-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 β-OH-5-HT in detail. The CD spectra showed no optical activity, suggesting a racemic mixture. To separate dl-β-OH-5-HT, we synthesized l-Ala-5-HT and derivatized it into erythro- and threo-l-Ala-β-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, β-OH-5-HT readily reacted with nucleophiles like alcohols or thiols, yielding a variety of dl-β-substituted-5-HT. The unusual properties of β-OH-5-HT might be attributed to the unique nature of a β-hydroxyl group adjacent to an indole ring and amino group. The mechanism for the rapid racemization of β-OH-5-HT is discussed.

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Abbreviations

5-HT:

5-Hydroxytryptamine or serotonin

β-OH-5-HT:

β-Hydroxy-serotonin

TSO:

Tryptophan side chain oxidase

FD/EI-MS:

A field disorption/electron ionization mass spectrometry

2D-NMR:

Two-dimensional nuclear magnetic resonance

β-OH-l-Trp:

β-Hydroxy-l-tryptophan

β-OH-l-5-HTP:

β-Hydroxy-l-5-hydroxytryptophan

5-HTP:

5-Hydroxytryptophan

Z:

Benzyloxycarbonyl

EDC-HCl:

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

TMS:

Trimethylsilane

β-keto-5-HT:

β-Ketoserotonin

r.t.:

Retention time

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Acknowledgments

This work was supported in part by Grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan (09270211 to KT and 15590267 to E. N–O.), the Naito Foundation (to E. N–O.), and American Heart Association Grant 11SDG5560001 (to E. N–O.). We thank Dr.s H. Tanno and T. Futamura for the bulk supply of Pseudomonas cells.

Conflict of interest

The authors declare no competing financial interest.

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Authors and Affiliations

  1. Johnson Research Foundation, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Rm 1009B Stellar-Chance Bldg., 422 Curie Boulevard, Philadelphia, PA, 19104, USA

    Jeremy Salinger & Eiko Nakamaru-Ogiso

  2. Department of Biomedical Chemistry, Institute of International Health, The University of Tokyo, Graduate School of Medicine, Tokyo, 113-0033, Japan

    Takaaki Kawashima, Katsuji Takai & Eiko Nakamaru-Ogiso

  3. Department of Experimental Nursing, Faculty of Nursing, Fukuoka Prefectural University, Tagawa, Fukuoka, 825-8585, Japan

    Koichi Hida & Eiko Nakamaru-Ogiso

Authors
  1. Takaaki Kawashima
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  2. Jeremy Salinger
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  3. Koichi Hida
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  4. Katsuji Takai
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  5. Eiko Nakamaru-Ogiso
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Correspondence to Eiko Nakamaru-Ogiso.

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Kawashima, T., Salinger, J., Hida, K. et al. Unusual reactivity of β-hydroxy-serotonin, a forgotten serotonin derivative. Amino Acids 47, 189–198 (2015). https://doi.org/10.1007/s00726-014-1854-4

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  • DOI: https://doi.org/10.1007/s00726-014-1854-4

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