nsc-4347 and Hyperpigmentation

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.

Topics: Acrylamides; Amides; Animals; Calcium; Dioxanes; Extracellular Signal-Regulated MAP Kinases; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Guinea Pigs; HEK293 Cells; Humans; Hyperpigmentation; Intramolecular Oxidoreductases; MAP Kinase Signaling System; Melanins; Mice; Models, Biological; Monophenol Monooxygenase; Phosphatidylinositol 3-Kinases; Phosphorylation; Piper; Proto-Oncogene Proteins c-akt; RNA, Messenger; Skin; TRPM Cation Channels