Exploration of Novel 3-Substituted Azetidine Derivatives As Triple Reuptake Inhibitors

Han, Young-Hue; Han, Minsoo; Shin, Dongyun; Song, Chi-Man; Hahn, Hoh‐Gyu

doi:10.1021/jm3008294

Cited by 48 publications

(16 citation statements)

References 25 publications

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“…All other reagents were of the highest purity among commercially available products. KHG26792 was synthesized and purified as described previously (19). KHG26792 was dissolved in DMSO and stored at –20°C as a stock solution (10 mM).…”

Section: Methodsmentioning

confidence: 99%

Protective effect of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on hypoxia-induced toxicity by suppressing microglial activation in BV-2 cells

Kim¹,

Kim²,

Na³

et al. 2016

BMB Reports

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We recently reported the anti-inflammatory effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on the ATP-induced activation of the NFAT and MAPK pathways through the P2X7 receptor in microglia. To further investigate the underlying mechanism of KHG26792, we studied its protective effects on hypoxia-induced toxicity in microglia. The administration of KHG26792 significantly reduced the hypoxia-induced expression and activity of caspase-3 in BV-2 microglial cells. KHG26792 also reduced hypoxia-induced inducible nitric oxide synthase protein expression, which correlated with reduced nitric oxide accumulation. In addition, KHG26792 attenuated hypoxia-induced protein nitration, reactive oxygen species production, and NADPH oxidase activity. These effects were accompanied by the suppression of hypoxia-induced protein expression of hypoxia-inducible factor 1-alpha and NADPH oxidase-2. Although the clinical relevance of our findings remains to be determined, these data results suggest that KHG26792 prevents hypoxia-induced toxicity by suppressing microglial activation.

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Section: Methodsmentioning

confidence: 99%

Protective effect of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on hypoxia-induced toxicity by suppressing microglial activation in BV-2 cells

Kim¹,

Kim²,

Na³

et al. 2016

BMB Reports

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“…KHG26792, 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride, was synthesized at the Organic Chemistry Laboratory (KIST, Seoul, Korea) [13], dissolved in DMSO, and stored at -20℃ as a stock solution (50 mM). Dulbecco's Modified Eagle's Medium (DMEM), Nutrient Mixture F-12 Ham, sodium bicarbonate, HEPES, formaldehyde, insulin, L-ascorbic acid, isoproterenol, hydrocortisone, 12-O-tetradecanoylphorbol-13-acetate (TPA), cholera toxin (CT), synthetic melanin, L-DOPA, and mushroom tyrosinase were obtained from Sigma (St Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

KHG26792 Inhibits Melanin Synthesis in Mel-Ab Cells and a Skin Equivalent Model

Kim

Hahn

et al. 2014

Korean J Physiol Pharmacol

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The purpose of this study is to characterize the effects of KHG26792 (3-(naphthalen-2-yl(propoxy) methyl)azetidine hydrochloride), a potential skin whitening agent, on melanin synthesis and identify the underlying mechanism of action. Our data showed that KHG26792 significantly reduced melanin synthesis in a dose-dependent manner. Additionally, KHG26792 downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase, the rate-limiting enzyme in melanogenesis, although tyrosinase was not inhibited directly. KHG26792 activated extracellular signal-regulated kinase (ERK), whereas an ERK pathway inhibitor, PD98059, rescued KHG26792-induced hypopigmentation. These results suggest that KHG26792 decreases melanin production via ERK activation. Moreover, the hypopigmentary effects of KHG26792 were confirmed in a pigmented skin equivalent model using Cervi cornus Colla (deer antler glue), in which the color of the pigmented artificial skin became lighter after treatment with KHG26792. In summary, our findings suggest that KHG26792 is a novel skin whitening agent.

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“…and the BBB crossing ability. In FST, compound 5 was able to reduce total immobility in a dose-dependent manner [119]. However, due to the presence of naphthyl groups, both compounds have inhibited hERG at low concentrations which may lead to serious side effects.…”

Section: Triple Reuptake Inhibitors As Potential Next-generation Antimentioning

confidence: 99%

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

Santra

Dutta

2015

Future Med. Chem.

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The current therapy for depression is less than ideal with remission rates of only 25–35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.

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Exploration of Novel 3-Substituted Azetidine Derivatives As Triple Reuptake Inhibitors

Cited by 48 publications

References 25 publications

Protective effect of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on hypoxia-induced toxicity by suppressing microglial activation in BV-2 cells

Protective effect of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride on hypoxia-induced toxicity by suppressing microglial activation in BV-2 cells

KHG26792 Inhibits Melanin Synthesis in Mel-Ab Cells and a Skin Equivalent Model

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

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