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Analyses of synthetic N-Acyl Dopamine derivatives reveal differential structural requirements for their anti-inflammatory and transient receptor potential channel of the vanilloid receptor subfamily subtype 1 (TRPV1) activating properties

Pallavi, P., Pretze, M., Caballero, J., Li, Y., Hofmann, B. B., Stamellou, E., Klotz, S., Wängler, C., Wängler, B., Loesel, R., Roth, S., Theisinger, B., Moerz, H., Binzen, U., Greffrath, W., Treede, R-D., Harmsen, M. C., Krämer, B. K., Hafner, M., Yard, B. A. & Kälsch, A-I., 2018, In : Journal of Medicinal Chemistry. 61, 7, p. 3126-3137 12 p.

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  • Analyses of synthetic N-Acyl Dopamine derivatives reveal differential structural requirements

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DOI

  • Prama Pallavi
  • Marc Pretze
  • Julio Caballero
  • Yingchun Li
  • Björn B Hofmann
  • Eleni Stamellou
  • Sarah Klotz
  • Carmen Wängler
  • Björn Wängler
  • Ralf Loesel
  • Steffen Roth
  • Bastian Theisinger
  • Handan Moerz
  • Uta Binzen
  • Wolfgang Greffrath
  • Rolf-Detlef Treede
  • Martin C Harmsen
  • Bernhard K Krämer
  • Mathias Hafner
  • Benito A Yard
  • Anna-Isabelle Kälsch

We studied the chemical entities within N-octanoyl dopamine (NOD) responsible for transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) activation and inhibition of inflammation. The efficacy of NOD to activate TRPV1 was significantly higher compared to variants in which the ortho-dihydroxy groups were acetylated, one of the hydroxy groups was omitted (N-octanoyl tyramine) or the ester functionality consisted of a bulky fatty acid (N-pivaloyl dopamine). Shortening of the amide linker (ΔNOD) slightly increased its efficacy which further increased by interchanging the carbonyl and amide groups (ΔNODR). With the exception of ΔNOD, the presence of an intact catechol structure was obligatory for inhibition of VCAM-1 and induction of HO-1 expression. Since TRPV1 activation and inhibition of inflammation by N-acyl dopamines require different structural entities, our findings provide a framework for the rational design of TRPV1 agonists with improved anti-inflammatory properties.

Original languageEnglish
Pages (from-to)3126-3137
Number of pages12
JournalJournal of Medicinal Chemistry
Volume61
Issue number7
Early online date15-Mar-2018
Publication statusPublished - 2018

    Keywords

  • Journal Article, REGION, PAIN, N-OCTANOYL-DOPAMINE, TRPV1 ION-CHANNEL, ANALGESIC AGENTS, AGONIST ACTIVITY, CAPSAICIN, ACTIVATION, HYPERALGESIA, ANALOGS

ID: 55720432