• 대한화학회지
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• 제42권1호
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• pp.64-68
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• 1998

한국 연해에 서식하고 있는 의충동물 개불(Urechis unicintus)로 부터 강심작용과 관련된 $Na^+,K^+-ATPase$ 저해 작용 및 cyclic AMP phosphodiesterase 저해 작용이 높은 anthraquinones화합물인 chrysophanol, physcion 및 1-o-methyl-2methoxychrysophanol을 분리하였다.주로 HMQC, HMBC 및 NOE 등의 분광학적 방법으로 이들의 구조를 밝혔다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1992년도 제1회 신약개발 연구발표회 초록집
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• pp.33-33
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• 1992

항혈전성 약물로서 그의 항 혈소판 작용력은 dipyridamole보다 강하나 심혈관계 등에 대한 부작용이 적어 clinical efficiency가 유의하게 높은 약물개발에 대한 연구는 임상적 응용성 뿐 아니라, 혈소판-응고기전의 규명에 기여할 것으로 사료되는 바 본 연구에서는 cyclic nucleotide phosphodiesterase(PDE-I)들의 항혈소판 작용을 검토하여 그들의 혈관 내피세포와 혈관평활 근세포의 중식에 대한 영향을 항혈소판성 작용을 보이며 혈관세포들의 증식에 없어서는 안되는 spermine의 그것과 비교 검색하였다. Johnson 등(1985)의 방법에 따라서 제조한 aequorin부하-가토혈소판의 thrombin(0.25 units: TB)에 대한 응집반응에서, pyridazinone 유도체인 KR30075, sodium nitroprusside(SNP), imazodan, isobutylmethylxanthine(IBMX), rolipram, 및 spermine의 응집억제성 $IC_{50}$/ (M)은 각각 2.21 $\times$ $10^{-7}$, 1.26 $\times$ $10^{-6}$, 6.96 $\times$ $10^{-6}$, 7.78 $\times$ $10^{-6}$, 8.11 $\times$ $10^{-4}$, 및 4.28 $\times$ $10^{-3}$ M으로써 이들은 TB-응고반응에 동반되는 혈소판 [Ca$^{++}$]$_{i}$-증가에 대한 각각의 $IC_{50}$/과 차이를 보이지 않았으며, 유의한 상관성을 보였다.

• BMB Reports
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• 제46권2호
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• pp.113-118
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• 2013

TTRAP is a multi-functional protein that is involved in multiple aspects of cellular functions including cell proliferation, apoptosis and the repair of DNA damage. Here, we demonstrated that the lentivirus-mediated overexpression of TTRAP significantly inhibited cell growth and induced apoptosis in osteosarcoma cells. The ectopic TTRAP suppressed the growth and colony formation capacity of two osteosarcoma cell lines, U2OS and Saos-2. Cell apoptosis was induced in U2OS cells and the cell cycle was arrested at G2/M phase in Saos-2 cells. Exogenous expression of TTRAP in serum-starved U2OS and Saos-2 cells induced an increase in caspase-3/-7 activity and a decrease in cyclin B1 expression. In comparison with wild-type TTRAP, mutations in the 5'-tyrosyl-DNA phosphodiesterase activity of TTRAP, in particular $TTRAP^{E152A}$, showed decreased inhibitory activity on cell growth. These results may aid in clarifying the physiological functions of TTRAP, especially its roles in the regulation of cell growth and tumorigenesis.

• Archives of Pharmacal Research
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• 제13권2호
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• pp.136-141
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• 1990

The vasorelaxant effects of KR-30075 in guinea-pig pulmonary, bovine coronary and renal arterial strips contracted by either$K^+$depolarization, phenylephrine, or prostaglandin $F_{2a}$($PGF_{2a}$) were evaluated. KR-30075 was more potent than imazodan as a vasorelaxant against $PGF_{2a}$-induced contractions in bovine coronary and renal arteries, whereas against$K^+$induced contractions KR-30075 was less potent than imazodan in guieapig pulmonary arteries and more potent in bovine coronary arteries. KR-30075 was more potent against contractions induced by phenylephrine or $PGF_{2a}$ than the contractions induced by $K^+$ This profile of activity for KR-30075 was similar to that of imazodan and dissimilar from the calcium entry blocking agent nifedipine. There was no vascular selectivity of KR-30075 between bovine coronary and renal arterial strip preparations. In conclusion, this study shows that KR-30075 represents the vasorelaxant effects on guinea-pig pulmonary, bovine coronary and renal arteries without specific vascular selectivity. The vasorelaxant profile of KR-30075, with different sources of vascular smooth muscle, is unlike that of calcium entry blocking agent and more similar to the profile of the agent that inhibit cyclic nucleotide phosphodiesterase.

• 대한화학회지
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• 제37권3호
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• pp.355-363
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• 1993

Whatmann chromatography paper(3MM)을 지지체로 사용하여 phosphite-triester법에 의해 미량의 염기가 부착된 5'-d(GAATTCCGGCCA)와 5'-d(GGAGCTGTC)의 두 oligodeoxyribonucleotide를 합성 하였다. Trityl yield 분석에 의하면 76.1${\%}$와 86.5${\%}$의 평균 coupling 수율을 각각 얻었다.두 oligodeoxyribonucleotide들을 HPLC를 이용하여 분리 정제할 수 있었고 snake venom phosphodiesterase와 bacterial alkaline phosphatase에 의해 분리 정량화할 수 있었으며 이때의 염기의 수는 합성을 시도한 염기수와 일치했다. 이처럼 paper를 지지체로 이용한 oligodeoxyribonucleotide의 합성은 값싸고 동시에 많은 염기가 부착된 미량의 DNA를 빠르고 짧은 기간에 수행할 수 있는 장점이 있다.

• Archives of Pharmacal Research
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• 제25권6호
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• pp.873-878
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• 2002

OA-8159, a new Phosphodiesterase (PDE) 5 inhibitor, has exhibited potent erectogenic potential in a penile erection test in rats and anesthetized dogs. In this study, we investigated the mechanism of its erectogenic activity by measuring the activity of OA-8159 against a various PDE isozymes and assessing cGMP and cAMP formation in a rabbit corpus cavernosum in vitro. DA-8159 inhibited the PDE 5 activity in rabbit and human platelets, which the $IC_{50}$ was 5.84$\pm$1.70 nM and 8.25$\pm$2.90 nM, respectively. The $IC_{50}$ of DA-8159 on PDE 1, PDE2, PDE 3 and PDE 6 were 870$\pm$57.4 nM, $101\pm$5 $\mu$M, 52.0$\pm$3.53 $\mu$M and 53.3$\pm$2.47 nM, respectively. This suggests that DA-8159 is a potent, highly selective, competitive inhibitor of PDE 5-catalyzed cGMP hydrolysis. The rates of cGMP hydrolysis catalyzed by human platelets-derived PDE 5 as a function of the cGMP concentration (5~100 nM) and two-fixed DA-8159 concentration (11.3 and 18.8 nM) were investigated in order to characterize the mode of PDE 5 inhibition by DA-8159. DA-8159 increased the apparent 4K_{m}$ value for cGMP hydrolysis but had no effect on the apparent $V_{max}$, indicating a competitive mode of inhibition. DA-8159 increased the cGMP concentrations in the rabbit corpus cavernosum dose dependently. In the presence of sodium nitroprusside (SNP), DA-8159 significantly sti\mulated the accu\mulation of cGMP when compared to the control level. This indicated that the enhancement of a penile erection by DA-8159 involved the relaxation of the cavernosal smooth \muscle by NO-sti\mulated cGMP accu\mulation. In conclusion, DA-8159 is a selective inhibitor of PDE 5-catalyzed cGMP hydrolysis and the enhancement of a penile erection by DA-8159 is mediated by the relaxation of the cavernosal smooth \muscle by the NO-sti\mulated cGMP accu\mulation.

• 생명과학회지
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• 제11권4호
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• pp.346-353
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• 2001

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) a prototype of the highly toxid halogenated arylhydrocarbons, bioaccumulates in the food chain and induces a complex spectrum of pathological responses. However, its effect on the nerve system is relatively not well studied. In this study we evaluated TCDDs cytotoxicity on the cortical cell and investigated its effect on the expression 2,3-cyclic nucleotide 3-phosphodiesterase(CNPase), a marker for oilgodendrocytes, The survival rates of 4 DIV cortical cells, that are dissociated from E18 rat cortex and maintained in the presence of TCDD, were 88.8, 83.6, 78.5, and 78.6%(5,10, 20 and 50 nM, respectively) where the reduction in 20 and 50mM TCDD were statistically very significant(p<0.01). Imunocytochemistry of cultured cells revealed that the intensities of immunostaining with an anti-CNP1&2 antibody depended on the concentrations of the toxin. Immunoblot analysis also showed differential expression of CNP1 and CNP2 in the presence of TCDD; the CNP1 expression was dose-dependently decreased. Interestingly, the expression of CNP2 in the presence if TDCC; the CNP1 expression was dose-dependently decreased. Interestingly, the expression of CNP2 fluctuated with the TCDD concentration. These results indicated that CNP1 and 2 are differentially regulated by TCDD, implying the functions of oligodendrocytes are modulated by the toxin.

• 대한약리학회지
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• 제32권3호
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• pp.373-380
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• 1996

최근 본 연구실에서는 GS 386인 1-(4'-methoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline이 적출된 토끼의 심방세포에서 $Ca^{++}$ 채널의 운동성 변화없이 $Ca^{++}$ 채널이 열릴 가능성을 줄임으로써 $Ca^{++}$ 전류의 증폭을 억제한다고 보고하였다. 이번 연구에서는 적출된 쥐의 기관지를 사용하여 GS 386의 작용기전에 대해 연구하였다. GS386은 carbachol $(0.3{\mu}M)$과 높은 농도의 $K^+$ (65.4mM)에 의해 수축된 쥐의 기관지를 용량-의존적으로 이완시켰으며 이때 $IC_{50}$는 5.24와 $5.67\;{\mu}M$이었다. verapamil은 carbachol에 의한 수축시 보다 높은 농도의 $K^+$에 의해 수축된 조직에 더욱 효과적으로 억제하였다. $Ca^{++}$이 없는 상태에서 $Ca^{++}$에 의한 수축은 GS386에 의해 억제되었다. 더욱이 높은 농도의 GS386$(100\;{\mu}M)$은 verapamil과는 다르게 carbachol뿐만 아니라 caffeine에 의한 위상성 수축을 억제 시키므로 GS386은 세포질내로 들어가 sarcoplasmic retuculum과 같은 근육 내부에 2차적인 영향을 나타내었다. 더군다나GS386은 verapamil에 의해 영향을 받지않는 (verapamil-insensitive component)이완을 보였고 쥐 기관지의 평활근에서 cAMP의 양을 증가 시켰다. 이러한 결과는 GS386의 작용기전이 $Ca^{++}$ 길항적인 작용 뿐만 아니라 posphodiesterase억제작용에 기인한다는 사실을 제시한다.

• 대한약리학회지
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• 제30권1호
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• pp.101-109
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• 1994

Tetrahydroisoquinoline유도체인 GS 283의 약리학적 특성을 흰쥐 흉부대동맥, 기니픽 결장띠 및 토끼 장간막 동맥 및 흰쥐 뇌를 사용하여 조사하였다. 혈관 평활근에서 GS283은 고 $K^+$에 의한 수축을 농도 의존적으로 억제하여 $Ca^{2+}$ 길항작용을 보였다. 또한 ${alpha}_1$- 수용체 자극에 의한 수축도 억제하였다. GS 283의 혈관이완 작용은 propranolol영향을 받지 않으므로 ${\beta}$-수용체 자극작용에 의한 것이 아니었다. 세포내 칼슘이온과 근장력 변화를 동시에 측정하였을 때 GS 283의 억제효과는 조직내 형광의 증가를 수반했다. 이 증가는 fura 2형광에 의한것이 아니라 내인성 pyridine nucleotide에 의한 것이며 이는 GS 283이 미토콘드리아 기능을 억제하는 효과가 있음을 시사했다. 흰쥐 뇌의 cAMP와 cGMP 의존성 phosphodiesterase에 대한 GS 283의 $K_i$,값은 2.5와 6.7mM이었다. 이상의 결과에서 GS 283의 약리 작용은 $Ca^{2+}$ 길항작용, ${\alpha}_1$- 수용체억제 작용 및 cyclic nucleotide 의존성 phosphodiesterase 억제 등 다양한 작용이 있으며 평활근 수축 억제에 대한 GS283 작용에는 $Ca^{2+}$ 길항이 가장 중요한 요인이 될 것으로 생각된다.

• The Korean Journal of Physiology and Pharmacology
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• 제10권3호
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• pp.149-154
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• 2006

Selective inhibition of phosphodiesterase (PDE) 5 opened a new therapeutic approach for cardiovascular disorders. Therefore, the effect of PDE5 inhibition on the cardiac function should thoroughly be defined. The purpose of the present study was to define the effects of sildenafil, a selective inhibitor of PDE5, on the atrial cGMP efflux, atrial dynamics, and the release of atrial natriuretic peptide (ANP). By perfusing rabbit left atria to allow atrial pacing, changes in atrial stroke volume and pulse pressure, transmural extracellular fluid translocation, cGMP efflux, and ANP secretion were measured. SIN-I, an NO donor and soluble (s) guanylyl cyclase (GC) activator, and C-type natriuretic peptide (CNP), an activator of particulate (p) GC activator, were used. Sildenafil increased basal levels of cGMP efflux slightly but not significantly. Sildenafil in a therapeutic dose increased atrial dynamics (for atrial stroke volume, $2.84{\pm}1.71%$, n=12, vs $-0.71{\pm}0.86%$, n=21; p<0.05) and decreased ANP release ($-9.02{\pm}3.36%$, n=14, vs $1.35{\pm}3.25%$, n=23; p < 0.05), however, it had no effect on the SIN-1- or CNP-induced increase of cGMP levels. Furthermore, sildenafil in a therapeutic dose accentuated SIN-1-induced, but not CNP-induced, decrease of atrial pulse pressure and ANP release. These data indicate that PDE5 inhibition with sildenafil has a minor effect on cGMP levels, but has a distinct effect on pGC-cGMP- and sGC-cGMP-induced contractile and secretory function.