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

Abstract

Melanogenesis 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-dihydroxybenzyl)-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.

Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model

“…The change in lightness (ΔL) value of the skin model was calculated from the L value (lightness index) measured by a colorimeter (CR-300; Konica Minolta, Tokyo, Japan), as follows: ΔL = L (treatment skin) − L (control skin) at 13 and 20 days. An increase in the ΔL value indicates the chemical-induced hypopigmentation of the skin [24]. …”

NF-κB/AP-1-Targeted Inhibition of Macrophage-Mediated Inflammatory Responses by Depigmenting Compound AP736 Derived from Natural 1,3-Diphenylpropane Skeleton

“…In a previous study, AP736 was shown to downregulate the expression of tyrosinase by inhibiting the cAMP-PKA-CREB signalling pathway [17]. In addition, AP736 has also been reported to strongly suppress melanin production [16].…”

“…Therefore, antimelanogenesis remedies would potentially be very valuable to the cosmetic and pharmaceutical industries. In this context, the small molecule AP736 (Figure 1) was recently synthesized from a 1,3-diphenylpropane skeleton through an optimization process involving the replacement of a phenyl group by dihydroxyl and adamantyl moieties [16]; importantly, AP736 was found to effectively suppress melanin production from melanocytes [17]. Although AP736 is clearly an effective depigmenting drug [16], it has not yet been determined whether it can suppress macrophage-mediated skin inflammatory responses, which are crucial for skin health [1].…”

S-(−)-10,11-Dihydroxyfarnesoic Acid Methyl Ester Inhibits Melanin Synthesis in Murine Melanocyte Cells

“…MITF possesses a basic helix–loop–helix structure for DNA binding, and plays a fundamental role in the transcriptional regulation of melanogenesis [22]. Endogenous cyclic AMP elevating stimuli such as α-MSH and ACTH promotes the expression of MITF through the activation of protein kinase A (PKA) and phosphorylates cAMP-related binding protein (CREB), which binds to the CRE consensus motif in the promoter region of MITF [23,24]. Our results show that dhFAME treatment dramatically reduced the expression of MITF mRNA as well as MC1R mRNA.…”