• 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.

• 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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• 제34권4호
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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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• 제17권6호
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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.

• 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.

• The Korean Journal of Physiology and Pharmacology
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• 제6권3호
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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.

• 한국동물위생학회지
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• 제18권2호
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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.

• 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.

• Bulletin of the Korean Chemical Society
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• 제35권7호
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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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• 제23권1호
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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.