• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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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.

• The Korean Journal of Pharmacology
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• v.30 no.1
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• pp.49-57
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• 1994

The binding properties of oxomemazine to muscarinic receptors using the ability of oxomemazine to inhibit $[^3H]QNB$ binding in membrane fractions of rat cerebrum and guinea pig ventricle and ileum were investigated. $[^3H]QNB$ bound to a single class of muscarinic receptors with a dissociation constant of approximately 60 pM in three tissue preparations. Pirenzepine and oxomemazine inhibited $[^3H]QNB$ binding in cerebrum with a Hill coefficient lower than unity, and the inhibition data were best described by a two-site model. The relative densities of the high $(M_1)\;and\;low\;(M_2)$ affinity sites for pirenzepine were 60 and 40%, with corresponding Ki values of 16 and 431 nM, and those $(O_H\;and\;O_L)$ for oxomemazine 40 and 60%, with corresponding Ki values of 80 and 1350 nM. However, the inhibition data of both drugs vs $[^3H]QNB$ in ventricle and ileum appeared to obey the law of mass-action (Hill coefficient close to 1). The apparent Ki values of pirenzepine were 850 and 250 nM, and those of oxomemazine 1460 and 570 nM in ventricle and ileum, respectively. Thus, oxomemazine like pirenzepine has high affinity for cerebrum, moderate affinity for ileum and low affinity for ventricle. These results suggest that oxomemazine could recognize the muscarinic receptor subtypes with a high affinity for the $M_1$ sites.

• YAKHAK HOEJI
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• v.34 no.4
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• pp.224-237
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• 1990

A single uniform population of specific, saturable, high affinity binding site of $[^3H]QNB$ guinuclidinyl benzilate(QNB) was identified in the rat cerebral microsomes. The Kd value(37.2 pM) for $[^3H]QNB$ calculated from the kinetically derived rate constants was in agreement with the Kd value(48.9 pM) determined by analysis of saturation isotherms at various receptor concentrations. Dimenhydrinate(DMH), histamine $H_1-blocker$, increased Kd value for $[^3H]QNB$ QNB without affecting the binding site concentrations and this effect resulted from the ability of DMH to slow $[^3H]QNB-receptor$ association. Pirenzepine inhibition curve of $[^3H]QNB$ binding was shallow(nH = 0.52) indicating the presence of two receptor subtypes with high ($M_1-site$) and low($M_2-site$) affinity for pirenzepine. Analysis of these inhibition curves yielded that 68% of the total receptor populations were of the $M_1-subtype$ and the remaining 32% of the $M_2-subtype$. Ki values for the $M_1-$ and $M_2-subtypes$ were 2.42 nM and 629.3 nM, respectively. Ki values for $H_1-blockers$ that inhibited $[^3H]QNB$ binding varied with a wide range ($0.02-2.5\;{\mu}M$). The Pseudo-Hill coefficients for inhibition of $[^3H]QNB$ binding by most of $H_1-blockers$ examined except for oxomemazine inhibition of $[^3H]QNB$ binding were close to one. The inhibition curve for oxomemazine in competition with $[^3H]QNB$ was shallow(nH = 0.74) indicating the presence of two receptor populations with different affinities for this drug. The proportion of high and low affinity was 33:67. The Ki values for oxomemazine were $0.045{\pm}0.016\;{\mu}M$ for high affinity and $1.145{\pm}0.232\;{\mu}M$ for low affinity sites. These data indicate that muscarinic receptor blocking potency of $H_1-blockers$ varies widely between different drugs and that most of $H_1-blockers$ examined are nonselective antagonist for the muscarinic receptor subtypes, whereas oxomemazine might be capable of distinguishing between subclasses of muscarinic receptor.

• Archives of Pharmacal Research
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• v.17 no.6
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• pp.443-451
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• 1994

The binding characteristics of pirenzepine and oxomemazine to muscarinic receptor were studied to evaluate the selectivity of oxomemazine for the muscarinic receptor subtypes in rat cerebral microsomes. Equililbrium dissociation constant $(K_D){\;}of{\;}(-)[^3H]$quinuclidinyl benzilate$([^3H)QNB)$ determined from saturation isotherms was 64-pM. Analysis of the pirenzepine inghibition curve of [$^3H$]QNB binding to cerebral microsome indicatd the presence of two receptor subtypes with high $(K_1 = 16 nM, M_1 receptor)$two receptor subypes with about 20-fold difference in the affinity for high $(k_1 = 84nM, {\;} O_H receptor){\;} and {\;}low{\;} (K_1{\;} ={\;} 1.65\muM, {\;} O_L receptor$) affinity sites. The percentage populations of $M_1{\;} and M_3$, /TEX> receptors to the total receptors were 61 : 39, and those of $O_H{\;} and{\;} O_L$ receptors 39 : 61, resepectively. Both pirenzepine and oxomemazine increaed the $K_D$ value for $[^3H]QNB$ without affecting the binding site concentrations and Hii coefficient for the $[^3H]QNB$ without affecting the binding site concentractions and Hill coefficient for the [$^{3}$H]QNB binding. Oxomemazine had a 10-fold higher affinity at $M_1$ receptors than at $M_3$ receptors, and pirenzepine a 8-fold higher affinity at $O_H$ receptors were of $O_H$ receptors and 71% of $M_3$ receptors. However, $M_3$for oxomemazine and $O_H$for pirenzepine were composed of a uniform population. These results suggest that oxomemazine could be classified as a selective drug for $M_1$ receptors and also demonstrate that rat cerebral microsomes contain three different subtypes of $M_1{\;} M_3$ and the other site which is different from $M_1, {\;} M_2$, /TEX> receptors.

• Journal of Life Science
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• v.21 no.4
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• pp.481-485
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• 2011

T0901317 is a potent synthetic ligand for liver X receptor (LXR, NR1H2/3), a member of the nuclear receptor superfamily that functions as a transcription factor. However, T0901317 has been also reported to modulate the activity at least four other nuclear receptors (NRs), acting as agonists for farnesoid X receptor (FXR, NR1H4) and pregnane X receptor (PXR, NR1I2) and as antagonists for androgen receptor (AR, NR3C4) and retinoid-related orphan receptor-${\alpha}$ (ROR-${\alpha}$, NR1F1). We report here that T0901317 can also function as an inhibitor for constitutive androstane receptor (CAR, NR1I3). Since CAR is a major player of xenobiotic and cholesterol metabolism in the liver, along with PXR, FXR and LXR, which are reported to be regulated by T0901317, this further complicates the interpretation of potential results with T0901317 in liver cells.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.3
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• pp.139-142
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• 2002

To examine intracellular signaling of human $S1P_3\;(hS1P_3),$ a sphingosine 1-phosphate (S1P) receptor in plasma membrane, $hS1P_3$ DNA was transfected into RH7777 rat hepatoma cell line, and the inhibition of forskolin-induced cAMP accumulation and activation of MAP kinases by S1P were tested. In $hS1P_3$ transformants, S1P inhibited forskolin-induced activation of adenylyl cyclase activity by about 80% and activated MAP kinases in dose-dependent and pertussis-toxin (PTX) sensitive manners. In oocytes expressing $hS1P_3$ receptor, S1P evoked $Cl^-$ conductance. These data suggested that PTX-sensitive G proteins are involved in $hS1P_3-mediated$ signaling, especially the positive action of S1P in cell proliferation. The potential advantages of rat hepatoma cells for the research of sphingosine 1-phosphate receptor are discussed.

• Korean Journal of Veterinary Service
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• v.18 no.2
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• pp.177-181
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• 1995

The effects of histamine were investigated on the uterine smooth muscle motility in the pig. The results were summarized as fellows : 1. Histamine caused the contraction of the porcine uterine smooth muscle and the contractile responses increased between the concetration of histamine $10^{-8}$ and $10^{-5}$ M with a dose-dependent manner. 2. The contractile response Induced by histamine ($10^{-6}$ M) was completely blocked by pretrevatment with $H_1$-histaminergic receptor blocker, pyrilamine($10^{-6}$ M) 3. The contractile response induced by histamine($10^{-6}$ M) was increased by pretreatment with $H_2$-histaminergic receptor blocker, cimetidine($10^{-6}$ M) From these results, it was concluded that the effects of uterine smooth muscle by histamine were the contraction mediated by $H_1$-histaminergic receptor and the relaxation mediated by $H_2$-histaminergic receptor in pig.

• YAKHAK HOEJI
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• v.39 no.6
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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.

• Bulletin of the Korean Chemical Society
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• v.35 no.7
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• pp.2025-2028
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• 2014

Anion receptor 1 based on acylhydrazone has been designed and synthesized. UV-vis and $^1H$ NMR titration showed that receptor 1 is selective receptor for dihydrogen phosphate ($H_2PO_4{^-}$). Dihydrogen phosphate was complexed by the receptor 1 via at least 4 hydrogen bonding interactions, contributing from two amide N-Hs and two imine C-Hs. In addition, nitrogen in the aromatic ring could make 2 additional hydrogen bondings with OH groups in the dihydrogen phosphate. However, the receptor 1 could make only 4 hydrogen bonds with halides. Therefore, receptor 1 could bind anions through hydrogen bonds with a selectivity in the order of $H_2PO_4{^-}$ > $Br^-$ > $Cl^-$ in highly polar solvent such as DMSO.

• Archives of Pharmacal Research
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• v.23 no.1
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• pp.31-34
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• 2000

An efficient procedure for the preparation of 7,8-dichloro-6-nitro-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione(7) as a potential lead compound for the NMDA receptor glycine binding site antagonist, starting from readily available 4,5-dichloro-2-nitroaniline(8), is described. The key step in the synthesis involves the cyclization of malonic ester amide 10 to compound 11.