A novel adamantyl benzylbenzamide derivative, AP736, suppresses melanogenesis through the inhibition of cAMP‐PKA‐CREB‐activated microphthalmia‐associated transcription factor and tyrosinase expression

• DOI: 10.1111/exd.12248
• Publication Date: 2013-10-11T22:08:56Z
• Authors: Chang Seok Lee; Won‐Hee Jang; Miyoung Park; Kyoungmi Jung; Heung Soo Baek; Yung Hyup Joo; Young‐Ho Park; Kyung‐Min Lim
• Keywords: Melanins; 0301 basic medicine; Microphthalmia-Associated Transcription Factor; Skin Neoplasms; Monophenol Monooxygenase; Melanoma, Experimental; Adamantane; Cyclic AMP-Dependent Protein Kinases; Mice; 03 medical and health sciences; Gene Expression Regulation; Hyperpigmentation; Cell Line, Tumor; Benzamides; Cyclic AMP; Animals; Humans; Melanocytes; Cyclic AMP Response Element-Binding Protein; Signal Transduction; Skin

AbstractMelanogenesis is essential for the protection of skin against UV, but excessive production of melanin causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we found that a tyrosinase inhibitor, AP736 (5‐adamantan‐1‐yl‐N‐(2,4‐dihydroxy‐benzyl)‐2,4‐dimethoxy‐benzamide) potently suppresses tyrosinase expression, and the mechanism underlying was elucidated. AP736 attenuated the melanin production induced by diverse melanogenic stimuli in murine and human melanocytes. It suppressed the expression of key melanogenic enzymes; tyrosinase, tyrosinase‐related protein‐1 and tyrosinase‐related protein‐2. The expression of microphthalmia‐associated transcription factor (MiTF), a major promoter of melanogenesis was also decreased. AP736 inhibited the activation of cAMP response element‐binding protein (CREB) and phosphokinase A (PKA), and cAMP elevation, reflecting that cAMP‐PKA‐CREB signalling axis was suppressed, resulting in the downregulation of MiTF and tyrosinase. Along with the previously reported tyrosinase inhibitory activity, the suppression of cAMP‐PKA‐CREB‐mediated MiTF and tyrosinase expression by AP736 may be efficient for the treatment for hyperpigmentation.