A novel synthetic Piper amide derivative NED-180 inhibits hyperpigmentation by activating the PI3K and ERK pathways and by regulating Ca2+ influx via TRPM1 channels

Pigment Cell Melanoma Res. 2016 Jan;29(1):81-91. doi: 10.1111/pcmr.12430.

Abstract

Piper amides have a characteristic, unsaturated amide group and exhibit diverse biological activities, including proliferation and differentiation of melanocytes, although the molecular mechanisms underlying its antimelanogenesis effect remain unknown. We screened a selected chemical library of newly synthesized Piper amide derivatives and identified (E)-3-(4-(tert-butyl)phenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (NED-180) as one of the most potent compounds in suppressing melanogenesis. In murine melan-a melanocytes, NED-180 downregulated the expression of melanogenic regulatory proteins including tyrosinase, Tyrp1, Dct, and MITF. PI3K/Akt-dependent phosphorylation of GSK3β by NED-180 decreases MITF phosphorylation and inhibits melanogenesis without any effects on cytotoxicity and proliferation. Furthermore, topical application of NED-180 significantly ameliorated UVB-induced skin hyperpigmentation in guinea pigs. Interestingly, data obtained using calcium imaging techniques suggested that NED-180 reduced the TPA-induced activation of TRPM1 (melastatin), which could explain the NED-180-induced inhibition of melanogenesis. All things taken together, NED-180 triggers activation of multiple pathways, such as PI3K and ERK, and inhibits TRPM1/TRPV1, leading to inhibition of melanogenesis.

Keywords: Piper amides; TRPM1; melanogenesis; skin-lightening agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Acrylamides / therapeutic use*
  • Amides / pharmacology
  • Amides / therapeutic use*
  • Animals
  • Calcium / metabolism*
  • Dioxanes / pharmacology
  • Dioxanes / therapeutic use*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • Hyperpigmentation / drug therapy*
  • Hyperpigmentation / enzymology
  • Intramolecular Oxidoreductases / metabolism
  • MAP Kinase Signaling System*
  • Melanins / metabolism
  • Mice
  • Models, Biological
  • Monophenol Monooxygenase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Piper / chemistry*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin / drug effects
  • TRPM Cation Channels / metabolism*

Substances

  • Acrylamides
  • Amides
  • Dioxanes
  • Melanins
  • NED-180
  • RNA, Messenger
  • TRPM Cation Channels
  • Monophenol Monooxygenase
  • Phosphatidylinositol 3-Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3
  • Intramolecular Oxidoreductases
  • dopachrome isomerase
  • Calcium