• Bulletin of the Korean Chemical Society
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• 제34권2호
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• pp.495-499
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• 2013

A novel series of aryl sulfonylpiperazine derivatives (5-15) were synthesized as 5-$HT_6$ ligands. In vitro assay was evaluated by measuring the 5-HT-induced $Ca^{2+}$ increases using HeLa cell line expressing the cloned human 5-$HT_6$ receptor, and the compound 13 showed potent 5-$HT_6$ receptor antagonistic effect with $IC_{50}$ value of 3.9 ${\mu}M$. Compound 13 also showed good selectivity on the 5-$HT_6$ over 5-$HT_4$ and 5-$HT_7$ receptors.

• Molecules and Cells
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• 제40권7호
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• pp.495-502
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• 2017

The $5-HT_6R$ has been considered as an attractive therapeutic target in the brain due to its exclusive expression in the brain. However, the mechanistic linkage between $5-HT_6Rs$ and brain functions remains poorly understood. Here, we examined the effects of $5-HT_6R$-mediated cell morphological changes using immunocytochemistry, Western blot, and live-cell imaging assays. Our results showed that the activation of $5-HT_6Rs$ caused morphological changes and increased cell surface area in HEK293 cells expressing $5-HT_6Rs$. Treatment with 5-HT specifically increased RhoA-GTP activity without affecting other Rho family proteins, such as Rac1 and Cdc42. Furthermore, live-cell imaging in hippocampal neurons revealed that activation of $5-HT_6Rs$ using a selective agonist, ST1936, increased the density and size of dendritic protrusions along with the activation of RhoA-GTP activity and that both effects were blocked by pretreatment with a selective $5-HT_6R$ antagonist, SB258585. Taken together, our results show that $5-HT_6R$ plays an important role in the regulation of cell morphology via a RhoA-dependent pathway in mammalian cell lines and primary neurons.

• Bulletin of the Korean Chemical Society
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• 제28권2호
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• pp.285-291
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• 2007

The 5-HT6 antagonists are mainly related to the treatment of cognitive dysfunction or impairment associated with Alzheimer's disease and schizophrenia. There have been lots of efforts to develop 5-HT6 antagonists. As in our efforts, arylsulfonylpiperazine derivatives 1-3 were designed, synthesized and biologically evaluated against the human recombinant 5-HT6 serotonin receptor. Total 36 compounds were synthesized and the most active compound among the synthesized compounds is compound 2h with an IC50 value of 1.5 μM. The compound 2h is novel as 5-HT6 receptor ligand and could act as lead for the novel 5-HT6 receptor ligands.

• 한국응용과학기술학회지
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• 제40권5호
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• pp.988-1000
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• 2023

Hesperetin은 Hesperidin에서 유도되는 강한 항산화 기능의 플라보노이드 비당체이다. 본 연구에서는 Hesperetin과 이의 Cyclodextrin 포접 복합체에 대하여 항산화, 항염증 및 항균 활성을 비교하였다. Hesperetin은 Hesperidin에 효소처리하여 제조되었으며, Hesperetin/Cyclodextrin 포접체는 용매 증류법에 의해 𝛽-Cyclodextrin 및 Hydroxypropyl-𝛽-Cyclodextrin을 사용하여 제조되었다. Hesperetin에 비해 Hesperetin/Hydroxypropyl-𝛽-Cyclodextrin 포접체의 용해도는 93.5배 증가하였고, Hesperetin/𝛽-Cyclodextrin 포접체의 용해도는 22.5배 증가하였다. 항산화 분석에서 Hydroxypropyl-𝛽-Cyclodextrin 포접체는 Hesperetin과 유사한 라디칼 소거 활성능을 보인 반면, 𝛽-Cyclodextrin 포접체는 Hesperetin 보다 약간 낮은 활성을 나타내었다. RAW 264.7 세포에 대한 세포독성은 Hydroxypropyl-𝛽-Cyclodextrin 포접체, 𝛽-Cyclodextrin 포접체, Hesperetin의 순으로 세포독성이 낮았다. Hesperetin과 Cyclodextrin 포접체는 모두 세포내 산화질소(NO), 종양괴사인자-𝛼(TNF-𝛼) 및 인터루킨-6(IL-6)과 같은 염증 매개체를 감소시켰다. Hesperetin 및 Hydroxypropyl-𝛽-Cyclodextrin 포접체는 상대적으로 𝛽-Cyclodextrin 포접체 보다 더 효과적이었다. 피부 유해성 세균인 황색 포도상구균과 녹농균에 대해 억제 효과를 시험한 결과, 황색 포도상구균에 대해서는 Hesperetin = Hydroxypropyl-𝛽-Cyclodextrin 포접체 > 𝛽-Cyclodextrin 포접체의 순서로 항균 효과를 나타내었으나, 녹농균에 대해서는 뚜렷한 억제효과를 나타내지 않았다. 결론적으로, Hesperidin의 비당체 형태인 Hesperetin과 이의 Cyclodextrin 포접체는 다양한 생물학적 활성을 보여주었으며, 용해도가 높은 Hydroxypropyl-𝛽-Cyclodextrin 포접체가 𝛽-Cyclodextrin 포접체에 비해 상대적으로 더 높은 활성을 나타내었다.

• The Korean Journal of Physiology and Pharmacology
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• 제19권6호
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• pp.523-531
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• 2015

Serotonin [5-hydroxytryptamine (5-HT)] regulates synaptic plasticity in the visual cortex. Although the effects of 5-HT on plasticity showed huge diversity depending on the ages of animals and species, it has been unclear how 5-HT can show such diverse effects. In the rat visual cortex, 5-HT suppressed long-term potentiation (LTP) at 5 weeks but enhanced LTP at 8 weeks. We speculated that this difference may originate from differential regulation of neurotransmission by 5-HT between the age groups. Thus, we investigated the effects of 5-HT on apha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-, ${\gamma}$-aminobutyric acid receptor type A (GABAAR)-, and N-methyl-D-aspartic acid receptor (NMDAR)-mediated neurotransmissions and their involvement in the differential regulation of plasticity between 5 and 8 weeks. AMPAR-mediated currents were not affected by 5-HT at both 5 and 8 weeks. GABAAR-mediated currents were enhanced by 5-HT at both age groups. However, 5-HT enhanced NMDAR-mediated currents only at 8 weeks. The enhancement of NMDAR-mediated currents appeared to be mediated by the enhanced function of GluN2B subunit-containing NMDAR. The enhanced GABAAR- and NMDAR-mediated neurotransmissions were responsible for the suppression of LTP at 5 weeks and the facilitation of LTP at 8 weeks, respectively. These results indicate that the effects of 5-HT on neurotransmission change with development, and the changes may underlie the differential regulation of synaptic plasticity between different age groups. Thus, the developmental changes in 5-HT function should be carefully considered while investigating the 5-HT-mediated metaplastic control of the cortical network.

• 한국생물물리학회:학술대회논문집
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• 한국생물물리학회 2003년도 정기총회 및 학술발표회
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• pp.59-59
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• 2003

Serotonin (5-HT; 5-hydroxytryptamine) exerts multiple effects on central nervous system as well as behaviors such as mood and appetite. The signaling of serotonin is mediated by 7 families of serotonin receptors, designated 5-HT$_1$ to 5-HT$_{7}$. Six families of this receptor are G-protein coupled 7TM receptors, and the third intracellular loop of these receptors is proposed to interact with specific types of G-proteins. To investigate the specific interaction between the third intracellular loop of 5-HT$_{6}$ with G$\square$s, we have constructed a chimera protein that represent the third intracellular loop of 5-HT$_{6}$ within a leucine zipper motifs, In addition an alpha subunit of human G-protein that interact with 5-HT$_{6}$ was cloned into a bacterial expression vector. The two proteins were expressed in E. coli and purified in homogeneity. The interaction of the prepared proteins was examined by ELISA assay. The affinity between the two proteins and effect of insertion mutations were discussed.ussed.d.

• The Korean Journal of Physiology and Pharmacology
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• 제23권6호
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• pp.509-517
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• 2019

Escitalopram is one of selective serotonin reuptake inhibitor antidepressants. As an S-enantiomer of citalopram, it shows better therapeutic outcome in depression and anxiety disorder treatment because it has higher selectivity for serotonin reuptake transporter than citalopram. The objective of this study was to determine the direct inhibitory effect of escitalopram on 5-hydroxytryptamine type 3 ($5-HT_3$) receptor currents and study its blocking mechanism to explore additional pharmacological effects of escitalopram through $5-HT_3$ receptors. Using a wholecell voltage clamp method, we recorded currents of $5-HT_3$ receptors when 5-HT was applied alone or co-applied with escitalopram in cultured NCB-20 neuroblastoma cells known to express $5-HT_3$ receptors. 5-HT induced currents were inhibited by escitalopram in a concentration-dependent manner. $EC_{50}$ of 5-HT on $5-HT_3$ receptor currents was increased by escitalopram while the maximal peak amplitude was reduced by escitalopram. The inhibitory effect of escitalopram was voltage independent. Escitalopram worked more effectively when it was co-applied with 5-HT than pre-application of escitalopram. Moreover, escitalopram showed fast association and dissociation to the open state of $5-HT_3$ receptor channel with accelerating receptor desensitization. Although escitalopram accelerated $5-HT_3$ receptor desensitization, it did not change the time course of desensitization recovery. These results suggest that escitalopram can inhibit $5-HT_3$ receptor currents in a non-competitive manner with the mechanism of open channel blocking.

• 한국식품저장유통학회지
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• 제22권4호
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• pp.559-566
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• 2015

본 연구에서는 곡류 중 트리코테센류 곰팡이독소인 T-2 독소 및 HT-2 독소의 LC-MS/MS 분석방법을 검증하고 국내 유통 곡류 중 T-2 독소 및 HT-2 독소의 오염실태를 파악하였다. 곡류 중의 T-2 독소 및 HT-2 독소를 분석하기 위해, 염화나트륨을 포함한 90% 메탄올 용액으로 추출, 원심분리, 여과, 4% 염화나트륨용액으로 희석하고, 원심분리한 후, 여과한 후 면역친화성칼럼에 의해 정제한 시료를 LC-MS/MS 동시정량 분석하였다. T-2 독소 및 HT-2 독소의 검출한계 및 정량한계는 각각 $0.5{\mu}g/kg$ 및 $1.5{\mu}g/kg$ 얻었다. matrix-matched 표준 검량식에서 상관계수 0.99 이상의 직선성을 얻었으며, T-2독소와 HT-2 독소 2배에서 10배의 정량한계로 표준용액을 첨가한 시료에서 회수율은 T-2독소와 HT-2 독소 각각 $100.6{\pm}7.2%$, $96.8{\pm}9.4%$로 EU 가이드라인에서 제시하는 유효성 기준을 만족하였다. LC-MS/MS 정량법을 이용하여 국내 곡류 9품목 115건에 대해 T-2 독소와 HT-2 독소의 오염도를 조사하여 본 결과, 전체 곡류 115건 중에서 T-2 독소는 83건, HT-2 독소는 93건 검출되었으며 오염도는 T-2 독소는 N.D~37.1 ug/kg, HT-2 독소는 N.D~5.4 ug/kg 으로 낮은 수준이었으며, 오염도는 유럽기준치($100{\mu}g/kg$)이내 이었다. 본 연구에서 개발된 곡류 중 T-2 독소 및 HT-2 독소에 대한 분석법은 향후 우리나라 곡류 중 곰팡이독소 안전관리를 위한 시험법으로 활용가능하며, 오염도 자료는 안전성 평가의 기초자료로 활용이 가능할 것으로 사료된다.

• Bulletin of the Korean Chemical Society
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• 제30권11호
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• pp.2707-2712
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• 2009

5-$HT_{3}$ receptor;5-$HT_{3A}$ receptor channel activity;Novel 5-$HT_{3}$ receptor channel current blockers;Chlorophenyl substituted piperazinylethylaminomethylpyrazoles; The 5-$HT_{3A}$ receptors are one of ligand-gated ion channels and are known to be involved in visceral pain, anxiety, or anticancer agent-induced nausea and vomiting. In present study, we designed novel skeletons based on the developed 5-$HT_{3}$ receptor antagonists and evaluated their effects on 5-$HT_{3A}$ receptor channel currents ($I_{5-HT}$) of a series of pyrazole derivatives having N-chlorophenylpiperazine functionality (6-9). We found that most of N-p-chlorophenyl substituted piperazinyl-pyrazole derivatives (7b, 7c, 7e and 7h) exhibited the high potency for the inhibition of $I_{5-HT}$, whereas the compound without chloride (6) or with m-chlorophenyl group (a serious of 8 and 9) showed the low potency. These result indicate that p-chlorophenyl group is might play an important role for increasing the inhibitory potency on $I_{5-HT}$.

• 생물정신의학
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• 제1권1호
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• pp.88-97
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• 1994

Many evidences are compatible with the correlation between the inhibition of [$^3H$] imipramine([$^3H$]IMI) and [$^3H$]paroxetine([$^3H$]PAT) binding to the 5-hydroxytryptamine(5-HT) transporter complex and the 5-HT uptake of 5-HT neurons and platelets, and most antidepressants have been shown to inhibit the [$^3H$]IMI and [$^3H$]PAT binding and the neuronal 5-HT uptake. However, several paradoxical research findings led to doubt about the pharmacological significance of the [$^3H$]IMI and [$^3H$]PAT binding sites. This study was carried to clarify the correlation between the [$^3H$]IMI and [$^3H$]PAT binding parameters and the tissue 5-HT content or/and [$^3H$]5-HT uptake in the rabbit platelet, which contains 40 times ad much 5-HT as that of human platelet and shows the 10 fold higher $B_{max}$ of the 5-HT transporter binding to a 5-HT uptake inhibitor. The rabbits were treated for 28 days with amitriptyline(4mg/kg/day : AP), fluoxetine(0.5mg/kg/day : FO), and sertraline(0.5mg/kg/day : SA) via an Alzet osmotic pump implanted for constant infusion. The [$^3H$]IMI binding $B_{max}$ and $K_d$ of the rabbit platelets were $6.4{\pm}1.2$pmol/mg protein and $10.9{\pm}2.1$nM and those in the [$^3H$]PAT binding were $8.6{\pm}1.1$pmol/mg protein and $1.6{\pm}0.3$nM, respectively. AP slightly increased $B_{max}$ of [$^3H$]IMI binding and both [$^3H$]IMI binding and [$^3H$]PAT binding $K_d$, and i contrast, it slightly decreased $B_{max}$ of [$^3H$]PAT binding. FO Slightly increased $K_d$ of both and [$^3H$]IMI and [$^3H$]PAT binding and slightly decreased $B_{max}$ of [$^3H$]IMI and [$^3H$]PAT binding. SA produced the significant increase of [$^3H$]PAT binding $B_{max}$ and the slight increase of both [$^3H$]IMI and [$^3H$]PAT binding $K_d$ and in contrast, it slightly decreased $B_{max}$ and of [$^3H$]IMI binding. And, the $V_{max}$ and $K_m$ of platelet [$^3H$]5-HT uptake were $24.2{\pm}2.4$pmol/$10^8$ platelets/min and $3.3{\pm}0.3$nM, respectively. The $V_{max}$ was little affected by AP, FO, or SA, but the [$^3H$]5-HT uptake $K_m$ value was moderately increased by FO. However, the platelet 5-HT content was moderately decreased by all of the 5-HT uptake inhibitors used in this study. These results seem to be consistent with the allosterical and competitive interaction of 5-HT uptake inhibiting antidepressants with each other as well as 5-HT in the 5-HT transporter binding, and provide no support for the view that the potencies of 5-HT uptake inhibitors to inhibit the [$^3H$]IMI or [$^3H$]PAT binding with 5-HT transporter complex correlate with their antidepressant potencies.