title: 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.
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.
authors.affiliation: Department of Oriental Medicinal Material and Processing, College of Life Science, Kyung Hee University, Yongin, Korea.
authors.forename: Eunson
authors.initials: E
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Yonsei University, Incheon, Korea.
authors.forename: Taek Hwan
authors.initials: TH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Korea.
authors.forename: Wook-Joo
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Korea.
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shim
authors.affiliation: Department of Biochemistry, College of Medicine, Gachon University, Incheon, Korea.
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Yeo
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Korea.|Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Korea.|Gachon Medical Research Institute, Gil Medical Center, Incheon, Korea.
authors.forename: Sun Yeou
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use*; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D017495:Hyperpigmentation / Q000188:drug therapy* / Q000201:enzymology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008543:Melanins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D014442:Monophenol Monooxygenase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D031701:Piper / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D000178:Acrylamides; D000577:Amides; D004146:Dioxanes; D008543:Melanins; C000611206:NED-180; D012333:RNA, Messenger; D050053:TRPM Cation Channels; D014442:Monophenol Monooxygenase; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase; D002118:Calcium
keywords: Piper amides; TRPM1; melanogenesis; skin-lightening agent