Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT2C receptor ligands for the treatment of obesity

Yang, Ha Yun; Tae, Jinsung; Seo, Yong Wan; Kim, Yoonjung; Im, Hye Yeon; Choi, Gil Don; Cho, Heeyeong; Park, Woo Kyu; Kwon, Oh‐Seung; Cho, Yong Seo; Ko, Minkyung; Jang, Hyun-Seo; Lee, Jaeick; Choi, Kihang; Kim, Chan Hwa; Lee, Jiyoun; Pae, Ae Nim

doi:10.1016/j.ejmech.2013.02.020

Cited by 22 publications

(9 citation statements)

References 13 publications

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“…'5-HT by acting on its multiple receptors exerts its effects to cells' is widely accepted. 5-HT 2 receptors in the hepatocyte and adipocyte are recognized as major receptors in 5-HT-induced IR 12,22,23 . Indeed, we also detected upregulated expression of 5-HT 2A R and 5-HT 2B R induced by Dex in the live, intra-abdominal adipose and BRL-3A cells (data in Figures S1 and S2).…”

Section: Discussionmentioning

confidence: 99%

Important role of 5‐hydroxytryptamine in glucocorticoid‐induced insulin resistance in liver and intra‐abdominal adipose tissue of rats

Li¹,

Guo²,

Qu³

et al. 2015

J of Diabetes Invest

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Aim/IntroductionBoth glucocorticoids and 5‐hydroxytryptamine (5‐HT) have been shown to induce insulin resistance (IR) in hepatocytes and adipocytes. Here, we explore whether there is a correlation between them.Materials and MethodsExcept for the control group, male rats were exposed to dexamethasone treated with or without para‐chlorophenylalanine (pCPA), or carbidopa for 20 days. Except for the control group, buffalo rat liver 3A (BRL‐3A) cells were exposed to dexamethasone for 24 h, treated with or without pCPA, carbidopa, or clorgiline for 48 h, or exposed to 5‐HT treated with or without fluoxetine for 48 h. Whole‐body IR was determined by both glucose tolerance test and measurement of fasting blood glucose and insulin, whereas hepatocytes or adipocytes IR was determined by examining either hepatic gluconeogenesis, steatosis and glucose transporter 2 expression or lipolysis.ResultsDexamethasone‐induced whole‐body IR, liver and intraabdominal adipose IR were accompanied by upregulated expressions of tryptophan hydroxylase‐1 and aromatic amino acid decarboxylase with increased 5‐HT level in both tissues, which were attenuated significantly by pCPA, inhibiting tryptophan hydroxylase‐1, or carbidopa, inhibiting aromatic amino acid decarboxylase. [Correction added on 22 September 2015, after first online publication: ‘inhibiting aromatic amino acid decarboxylase’ was duplicated and has been replaced by ‘tryptophan hydroxylase‐1’.] In the BRL‐3A cells, dexamethasone‐induced IR was also accompanied by upregulated 5‐HT synthesis in dose‐ and time‐dependent manners, and was attenuated by pCPA or carbidopa, but exacerbated by clorgiline, inhibiting monoamine oxidase‐A to further increase 5‐HT level. Dexamethasone also enhanced 5‐HT 2A and 2B receptor expressions in both tissues and BRL‐3A cells. Additionally, blocking 5‐HT transporter with fluoxetine significantly suppressed 5‐HT‐induced IR in BRL‐3A cells.ConclusionEnhancement of 5‐HT synthesis in liver and intra‐abdominal adipose is an important reason for glucocorticoids‐induced IR.

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Section: Discussionmentioning

confidence: 99%

Important role of 5‐hydroxytryptamine in glucocorticoid‐induced insulin resistance in liver and intra‐abdominal adipose tissue of rats

Li¹,

Guo²,

Qu³

et al. 2015

J of Diabetes Invest

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“…Many synthetic drugs such as Orilistat and Lorcaserin [12,13] are available for the treatment of hyperlipidemia, but all of them have serious side effects [14,15]. Thus, there is a need to develop new synthetic hypolipidemic agents with fewer or no side effects.…”

Section: Introductionmentioning

confidence: 99%

Hypolipidemic effect of dihydroisoquinoline oxaziridine in high-fat diet-fed rats

Aydi

Gara

Chaaben

et al. 2016

Biomedicine & Pharmacotherapy

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“…The most enriched set of dual blood stage inhibitors (cluster ID 8128) contains a pyrimidoazepine substructure, previously described as a serotonin receptor antagonist but not known to have antimalarial activity. 54 A thiophene heterocycle adjacent to the tertiary amine was potent under 1 μM in both blood stages (DDD01243664), with imidazole (DDD01254777) and thiazole/pyrazole (DDD01258014/DDD01255965; p = 6.11 × 10 −10 ) substitutions favoring potency in ABS and GAMs, respectively. Another GAM inhibitory cluster with at least one potent ABS member (cluster ID 2587) boasts a pyridinethiazole core, similar to previously known ABS potent scaffolds MMV007907, MMV001246, and MMV665909.…”

Section: ■ Resultsmentioning

confidence: 99%

Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials

et al. 2020

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Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compounds active against the ABS are then sequentially tested in more difficult assays that predict whether a compound has other beneficial attributes. Although applying this strategy to new chemical libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small molecules from the Global Health Chemical Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addition, instead of using an asexual assay that measures accumulated parasite DNA in the presence of compound (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compounds. Among 382 scaffolds with the activity confirmed by dose response (<10 μM), we discovered 68 novel delayed-death, 84 liver stage, and 68 stage V gametocyte inhibitors as well. Although 89% of the evaluated compounds had activity in only a single life cycle stage, we discovered six potent (half-maximal inhibitory concentration of <1 μM) multistage scaffolds, including a novel cytochrome bc1 chemotype. Our data further show the luciferase-based assays have higher sensitivity. Chemoinformatic analysis of positive and negative compounds identified scaffold families with a strong enrichment for activity against specific or multiple stages.

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Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT2C receptor ligands for the treatment of obesity

Cited by 22 publications

References 13 publications

Important role of 5‐hydroxytryptamine in glucocorticoid‐induced insulin resistance in liver and intra‐abdominal adipose tissue of rats

Important role of 5‐hydroxytryptamine in glucocorticoid‐induced insulin resistance in liver and intra‐abdominal adipose tissue of rats

Hypolipidemic effect of dihydroisoquinoline oxaziridine in high-fat diet-fed rats

Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials

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