• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1993년도 제2회 신약개발 연구발표회 초록집
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• pp.87-87
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• 1993

항 Histamine쟤의 효과적인 응용과 그 개발율 위한 자료를 얻고자 이들 약물의 H$_1$-receptor와 muscarinic receptor에 대한 작용의 상대적 역가를 비교하였다. 본 실험에 이용된 기니픽 회장에는 [$^3$H]QHB어 대한 단일 muscarinic receptor가 존재하였으며 [$^3$H]QNB의 affinity와 결합부위농도는 각각 54 pM 및 156 fmol/mg이었다. 항 histamine제는 muscarinic receptor에 대한 [$^3$H]QNB결합을 억제하였으며 [$^3$H]QNB 결합억제로부터 추정된 항 histamine제의 Ki치가 0.008$\mu$M-1.6$\mu$M로서 항 histamine제의 종류에 따라 현저한 차이가 있었고, 이 결과는 carbachol 반응억제로부터 추정된 각 항 histamine제의 muscarinic receptor에 대한 affinity(K$_{M}$)와 유사하였다. 한편 histamine수축반응 억제로부터 추정된 항 histamine재의 H$_1$-receptor에 대한 affinity(K$_{H}$ ) 역시 0.15nM-56.5nM로서 약물에 따라 차이가 있었고 각 약물의 $K_{M}$ /K$_{H}$ 비가 3-2300으로 H$_1$-receptor에 대한 역가와 muscarinic receptor에 대한 역가 사이에는 상관성이 없었다. 즉 유사한 항 allergy 작용을 일으킬 수 있는 치료혈중농도에서도 muscarinic receptor 차단작용이 다르며 본 실험에 사용한 13종의 기존 항 histamine제중 triprolidine이 $K_{M}$ /K$_{H}$ 비가 가장 높았고 diphenidol이 가장 낮았다. 이상의 결과로 보아 항 histamine제의 muscarinic receptor 차단작용은 이들 약물의 항 alleragy 효과에 필요한 작용이 아니며 본 실험에서 추정된 항 histamine제의 H$_1$-receptor와 muscarinic receptor에 대한 상대적 역가는 이들 약물의 선택과 평가에 중요한 지표가 될수 있을 것으로 생각된다.

• 생명과학회지
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• 제21권4호
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• pp.481-485
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• 2011

T0901317은 핵수용체 전사인자인 liver X receptor (LXR, NR1H2/3)의 강력한 합성 리간드이다. 그러나, T0901317은 farnesoid X receptor (FXR, NR1H4)와 pregnane X receptor (PXR, NR1I2)에 대해 작용물질(agonist) 로, androgen receptor (AR, NR3C4)와 rertinoid-related orphan receptor-${\alpha}$ (ROR-${\alpha}$, NR1F1)에 대해 길항제(antagonist)로 작용하여, LXR외에 적어도 다른 4종의 핵수용체에 대해 그 활성을 조절한다고 보고되었다. 우리는 T0901317이 또 다른 핵수용체인 constitutive androstane receptor (CAR, NR1I3)에 대해 저해제로 기능함을 확인 하였다. CAR는 이미 T0901317에 의해 기능이 조절된다고 알려진 PXR, FXR, LXR과 더불어 간에서 생체이물과 콜레스테롤의 대사작용에 중요한 역할을 하므로 T0901317에 의해 CAR의 활성이 조절된다는 사실은, 간세포에서 T0901317을 이용한 실험 결과를 해석할 때 세포 내에 이미 존재하는 이들 핵수용체 단백질의 영향을 고려하여 주의깊게 해석해야 함을 의미한다.

• 한방비만학회지
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• 제2권1호
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• pp.43-52
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• 2002

Purpose & Methods: In order to study obese gene mutation rate in obese Korean patients and to investigate the effect at Chegamuiyiin-tang and electro-lipolysis-acupuncture on obesity treatment. the difference of the reaction to herbal dieting between patients with ${\beta}3$ adrenergic receptor mutation and the patients with wild type ${\beta}3$ adrenergic receptor is observed. Results: Chegamuiyiin-tang and electro-lipolysis-acupuncture treatment are effective on the treatment of obesity in weight reduction. body fat reduction and the circumferences of arm, abdomen, hip and thigh. In the comparison of ${\beta}3$ adrenergic receptor wild type and ${\beta}3$ adrenergic receptor mutation groups, body fat was more reduced with statistical significance, and as for BMI change and body weight change were higher in ${\beta}3$ adrenergic receptor mutation groups with no statistical significance. In the comparison of ${\beta}3$ adrenergic receptor wild type and ${\beta}3$ adrenergic receptor mutation groups among BMI under 25 patients change rate of body weight. BMI, body fact percentage, WHR and body circumference were higher in ${\beta}3$ adrenergic receptor mutation group than in ${\beta}3$ adrenergic receptor wild type group. Conclusion: These results imply that herbal dieting program combined with electro-lipolysis-acupuncture is more effective on reducing body weight and body fat in ${\beta}3$ adrenergic receptor mutation group than wild type group, and that the earlier the treatment is applied, the more effective it is.

• Natural Product Sciences
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• 제27권2호
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• pp.134-139
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• 2021

A new cipadesin limonoid, i.e. 3-epi-cipadonoid C (1), and a new tirucallane triterpene, i.e. hispidol B 3-palmitate (3), have been isolated from the seeds and fruit peels extract of Sandoricum koetjape, respectively. Along with these compounds the known limonoid, cipaferen G (2), and two pentacyclic triterpenes, bryonolic (4) and bryononic (5) acids, were also isolated. The strucrures of the new compounds were elucidated by the analysis of NMR and mass spectral data. Compounds 1 - 5 were evaluated as the inhibitor of receptor tyrosine kinases (EGFR, Epidermal Growth Factor Receptor; HER2, HER4, Human Epidermal growth factor Receptor 2, -4; IGFR, Insulin-like Growth Factor Receptor; InsR, Insulin Receptor; KDR, Kinase insert Domain Receptor; PDGFRα, and PDGFRβ, Platelet-Derived Growth Factor Receptor-α and -β). The results showed only 1 and 3 that have weak activity against InsR.

• EDISON SW 활용 경진대회 논문집
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• 제2회(2013년)
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• pp.13-24
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• 2013

Dopamine agonists and antagonists and its receptor play a critical role in the information transfer in the nervous system, and dopamine receptor-ligands interactions are deeply related to Parkinson's disease, schizophrenia and some other mental diseases. However, the only experimental 3D structure available for dopamine receptors is human D3 dopamine receptor. Therefore, it is important to create model of subtype dopamine receptor-ligands interactions. We report here the 3D structures of the human D1 and D2 dopamine receptor predicted by using GalaxyTBM, and its predicted binding site determined by using GalaxyDock. The highly conserved Asp on TM 3 and Phe on TM 6 have critical role in ligand binding. Also, highly conserved serines on TM 5 are essential for binding agonists and some kinds of antagonists. We identify differences between binding sites of agonists and antagonists of human D1 and D2 dopamine receptor, and find the reasons of selective binding of antagonists.

• The Korean Journal of Physiology and Pharmacology
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• 제23권5호
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• pp.419-426
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• 2019

Mosapride accelerates gastric emptying by acting on 5-hydroxytryptamine type 4 ($5-HT_4$) receptor and is frequently used in the treatment of gastrointestinal (GI) disorders requiring gastroprokinetic efficacy. We tested the effect of mosapride on 5-hydroxytryptamine type 3 ($5-HT_3$) receptor currents because the $5-HT_3$ receptors are also known to be expressed in the GI system and have an important role in the regulation of GI functions. Using the whole-cell voltage clamp method, we compared the currents of the $5-HT_3$ receptors when 5-HT was applied alone or was co-applied with mosapride in cultured NCB-20 cells known to express $5-HT_3$ receptors. The $5-HT_3$ receptor current amplitudes were inhibited by mosapride in a concentration-dependent manner. Mosapride blocked the peak currents evoked by the application of 5-HT in a competitive manner because the $EC_{50}$ shifted to the right without changing the maximal effect. The rise slopes of $5-HT_3$ receptor currents were decreased by mosapride. Pre-application of mosapride before co-application, augmented the inhibitory effect of mosapride, which suggests a closed channel blocking mechanism. Mosapride also blocked the opened $5-HT_3$ receptor because it inhibited the $5-HT_3$ receptor current in the middle of the application of 5-HT. It accelerated desensitization of the $5-HT_3$ receptor but did not change the recovery process from the receptor desensitization. There were no voltage-, or use-dependency in its blocking effects. These results suggest that mosapride inhibited the $5-HT_3$ receptor through a competitive blocking mechanism probably by binding to the receptor in closed state, which could be involved in the pharmacological effects of mosapride to treat GI disorders.

• The Korean Journal of Physiology and Pharmacology
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• 제22권5호
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• pp.585-595
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• 2018

Amitriptyline, a tricyclic antidepressant, is commonly used to treat depression and neuropathic pain, but its mechanism is still unclear. We tested the effect of amitriptyline on 5-hydroxytryptamine 3 ($5-HT_3$) receptor currents and studied its blocking mechanism because the clinical applications of amitriptyline overlapped with $5-HT_3$ receptor therapeutic potentials. Using a whole-cell voltage clamp method, we recorded the currents of the $5-HT_3$ receptor when 5-HT was applied alone or co-applied with amitriptyline in cultured NCB-20 neuroblastoma cells known to express $5-HT_3$ receptors. To elucidate the mechanism of amitriptyline, we simulated the $5-HT_3$ receptor currents using Berkeley $Madonna^{(R)}$ software and calculated the rate constants of the agonist binding and receptor transition steps. The $5-HT_3$ receptor currents were inhibited by amitriptyline in a concentration-dependent, voltage-independent manner, and a competitive mode. Amitriptyline accelerated the desensitization of the $5-HT_3$ receptor. When amitriptyline was applied before 5-HT treatment, the currents rose slowly until the end of 5-HT treatment. When amitriptyline was co-applied with 5-HT, currents rose and decayed rapidly. Peak current amplitudes were decreased in both applications. All macroscopic currents recorded in whole cell voltage clamping experiments were reproduced by simulation and the changes of rate constants by amitriptyline were correlated with macroscopic current recording data. These results suggest that amitriptyline blocks the $5-HT_3$ receptor by close and open state blocking mechanisms, in a competitive manner. We could expand an understanding of pharmacological mechanisms of amitriptyline related to the modulation of a $5-HT_3$ receptor, a potential target of neurologic and psychiatric diseases through this study.

• 대한약리학회지
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• 제30권1호
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• pp.49-57
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• 1994

Oxomemazine이 muscarinic receptor subtypes에 대하여 선택성을 가지는지에 관한 지견을 얻고자, 대뇌, 심실 및 회장 muscarinic receptor에 대한 oxomemazine의 결합성질을 조사, 비교하였다. $[^3H]QNB$ 포화결합실험 결과 세 조직의 muscarinic receptor는 $[^3H]QNB$에 대해서는 affinity가 약 60pM인 단일 receptor인 것으로 추정되었다. 대뇌에서 pirenzepine과 oxomemazine의 $[^3H]QNB$ 결합억제에 대한 Hill coefficient는 각각 0.67 및 0.8로서 대뇌에는 이들 약물에 대하여 affinity가 서로 다른 두 종류의 muscarinic receptor subtypes가 존재하는 것으로 나타났으며, pirenzepine에 대한 high $affinity(M_1)$와 $low affinity(M_2)$ receptor 및 oxomemazine에 대한 high $affinity(O_H)$와 $low\;affinity (O_L)$ receptor의 분포비는 약 60:40 및 40:60이었고, $M_1$과 $M_2$ receptor에 대한 pirenzepine의 $K_i$치는 16nM 및 431 nM, $O_H$와 $O_L$, receptor에 대한 oxomemazine 의 $K_i$치는 80nM 및 1350nM이었다. 그러나 심실과 회장에서 이들 약물의 $[^3H]QNB$ 결합억제에 대한 Hill coefficient는 1에 가까웠다. 심실과 회장 muscarinic receptor에 대한 pirenzepine의 $K_i$치는 850nM 및 250nM, oxomemazine의 $K_i$치는 1460nM 및 670nM로서 대피에서 이들 약물의 low affinity receptor에 대한 $K_i$치에 가까웠다. 즉, muscarinic receptor에 대한 affinity면에서 oxomemazine은 pirenzepine과 같이 대뇌에서 가장 높았으며, 회장에 대해서는 중등도였고, 심실에서 가장 낮았다. 이로 보아 oxomemazine은 $M_1\;receptor$에 선택성이 있는 것으로 추정된다.

• 약학회지
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• 제39권6호
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• pp.645-653
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• 1995

Dibenamine inhibited [$^{3}$H]quinuclidinyl benzilate ([$^{3}$H]QNB) binding in both concentration and incubation time-dependent manners. The $IC_{50}$/ value of dibenamine for the inhibition of the specific binding of 100 pM [$^{3}$'H]QNB following incubation of cerebral microsomes with dibenamine at 37.deg. C for 15 min was 20.mu.M. Dibenamine irreversibly decreased the binding site concentration for [$^{3}$H]QNB binding without affecting the affinity of [$^{3}$H]QNB for the muscarinic receptor. Analysis of the pirenzepine inhibition curve of [$^{3}$H]QNB binding to cerebral microsomes indicated the presence of two receptor subtypes with high(M$_{1}$ receptor, Ki=5nM) and low (M$_{2}$ receptor, Ki=160nM) affinity for pirenzepine. However, dibenamine(20.mu.M) treatment under the condition employed in these experiments caused steepening of the pirenzepine competition curve. The Ki value for pirenzepine in dibenamine treated-microsomes was approximately 120nM. suggesting a selective decrease in the number of M$_{1}$ receptor. Although dibenamine also inhibited [$^{3}$H]QNB binding to ventricular microsomes with $IC_{50}$/ value of 120.mu.M, the sensitivity for dibenamine in the ventricle was much lower than that in the cerebrum. These results indicate that dibenamine at low concentrations welectively inactivates the muscarinic M$_{1}$ receptor.

• Biomolecules & Therapeutics
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• 제4권1호
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• pp.103-109
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• 1996

To investigate the effect of the third intracellular loop (i3 loop) peptide of human $\beta$$_2$-adrenergic receptor on receptor agonist binding, we expressed third intracellular loop region of human $\beta$$_2$-adrenergic receptor as glutathione S-transferase fusion protein in E. coli. DNA fragment of the receptor gene which encodes amino acid 221-274 of human $\beta$$_2$-adrenergic receptor was amplified by polymerase chain reaction and subcloned into the bacterial fusion protein expression vector pGEX-CS and expressed as a form of glutathione-S-transferase (GST) fusion protein in E. coli DH5$\alpha$. The receptor fusion protein was identified by SDS-PAGE and Western blot using monoclonal anti-GST antibody. The fusion protein expressed in this study was purified to an apparent homogeneity by glutathione Sepharose CL-4B affinity chromatography. The purified i3 loop fusion proteins at a concentration of 10 $\mu\textrm{g}$/ι caused right shift of the isoproterenol competition curve of [$^3$H]Dihydroalprenolol binding to hamster lung $\beta$$_2$-adrenergic receptor indicating lowered affinity of isoproterenol to $\beta$$_2$-adrenergic receptor possibly due to the uncoupling of receptor and G protein in the presence of the fusion protein. The uncoupling of receptor and G protein suggests that i3 loop region plays a critical role on $\beta$$_2$-adrenergic receptor G protein coupling.