• Proceedings of the Korean Society of Toxicology Conference
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• 2002.05a
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• pp.114-114
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• 2002

Inhibitors of type IV phosphodiesterase (PDE IV) are currently being developed as new therapeutic agents for asthma, chronic obstructive pulmonary disease(COPD) and arthritis. Unfortunately, the anti-inflammatory effect of PDE IV inhibitors has been considered to be associated to some extent with vomiting as adverse effect. The first generation PDE IV inhibitor, rolipram, was known to induce emesis at clinical trials. (omitted)

• Archives of Pharmacal Research
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• v.23 no.4
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• pp.332-337
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• 2000

This study describes the synthesis, in vitro evaluation and molecular modeling study of novel compounds for the inhibition of TNF-$\alpha$production, Among these compounds, 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone (9) was selected as a lead compound and its pyridine derivative 10 was more potent in activity and safer than rolipram.

• YAKHAK HOEJI
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• v.49 no.1
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• pp.109-113
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• 2005

In the present study treatment of IBMX, a phosphodiesterase (PDE) inhibitor, alone induced osteoclast formation in co-cultures of mouse bone marrow cells and calvarial osteoblasts. However, treatment of IBMX in combination with prostaglandin $E_2\;(PGE_2)$ inhibited osteoclast formation in a dose-dependent manner. Among various isozyme-specific PDE inhibitors, a PDE4 specific inhibitor, rolipram, showed similar effects as IBMX on osteoclast formation. To address the involvement of cyclic adenosine monophosphate (cAMP) in osteoclast formation, cAMP concentration in calvarial osteoblasts was investigated. When calvarial osteoblasts were co-cultured with IBMX alone or in combination with $PGE_2$, the patterns of cAMP concentration in calvarial osteoblasts were differ each other suggesting that cAMP in calvarial osteoblasts subtly regulates osteoclast formation.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.4
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• pp.429-437
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• 2017

The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4- dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)- 3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-$F2{\alpha}$ ($PGF2{\alpha}$)-induced phasic, $K^+$-induced tonic, and $Ca^{2+}$-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ ($TNF{\alpha}$) and interleukin (IL)-$1{\beta}$, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced $TNF{\alpha}$ and $IL-1{\beta}$ uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.155-155
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• 1993

항우울약인 rolipran(RP)등 phosphodiesterase-억제 약(PDE-1)들이 thrombin(TB: 0.25 U/ml)에 의한 혈소판 응집에 미치는 작용을 가토-혈소판에서 일차 검토하였다. 신 PDE-1인 KR-30075(KR)의 $IC_{50}$/은 sodim nitroprusside의 것보다 낮았고 PDE-1들은 혈소판내 cAMP와 cGMP를 증가시켰으며 특히 KR은 타 PDE-1와 달리 I $P_3$를 감소시켰다. 아울러 rolipram은 cGMP와 I $P_3$를 증가시켰으나, amitriptyline(AT), sertraline(57), chlorpromazine(CP) 및 spermine은 I $P_3$를 증가시켰다. 그러나 이들과 PDE-1들은 강도의 차이는 있으나 모두 TB에 의한 혈소판응집을 모두 억제하였다. 따라서, PDE-1 중 IBMX(2$\times$$10^{-5}$M), KR(5$\times$10$_－7/M), 및 rolipram(10$_{-3}$M) 그 외에 항우울약인 AT(1.5 $\times$10$_－4/M) 와 ST(10$_－4/M) 및 항정신병약인 CP(10$_－4/M)둥이 혈소판내 I $P_3$, [C $a^{＋＋}$], Tx $B_2$, 및 PG $I_2$ 함량과 단백-인산화의 TB에 의한 변동에 미치는 영향을 검토하였다. 그 결과 TB에 의한 혈소판내 I $P_3$, [C $a^{＋＋}$], Tx $B_2$, 및 PG $I_2$ 함량의 증가가 PDE-1들과 항우울약들에 의하여 억제되었다 단, 항우울성약들과 CP는 정상 혈소판 I $P_3$를 증가시켰다. 아울러 혈소판-단백인산학에서 TB는 41-43 kD와 20 kD의 인산화를 현저히 증가시키며 19 kD의 인산화는 감소시켰고, PKC의 기질인 41-43 kD와 20 kD의 단백인산화가 PDE-1들과 항우울약들 뿐 아니라 CP에 의하여 현저히 억제되었다. 단, 20 kD 인산화에 대한 AT의 억제작용은 미약하였고, cAMP와 PDE-1들은 22kD 인산화를 증가시켰다. AT, ST, 및 CP는 A23187에 의한 41-43 kD 인산화는 현저히 억제하나 20 kD 인산화에는 영향을 미치지 않았고, PMA(3.2$\times$$10^{－7}$ M)에 의한 단백인산화에 대하여는 더 미약한 억제-효과를 나타내었다. 이상의 결과는 PDE-1과 항우울약들의 항혈소판작용은 PKC-기질인 41-43 kD와 20 kD의 인산화를 억제함에 기인되는 것으로 사료된다.다. 것으로 사료된다.다.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1992.05a
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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.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.3
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• pp.225-231
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• 1997

As it has been reported that the depolarization-induced norepinephrine (NE) release is modulated by activation of presynaptic $A_1-adenosine$ heteroreceptor and various lines of evidence indicate the involvement of adenylate cyclase system in $A_1-adenosine$ post-receptor mechanism in hippocampus, it was attempted to delineate the role of adenylate cyclase system in the $A_1-receptor-mediated$ control of NE release in this study. Slices from rat hippocampus were equilibrated with $[^3H]-NE$ and the release of the labelled products was evoked by electrical stimulation.(3 Hz, $5Vcm^{-1}$, 2 ms, rectangular pulses). The influence of various agents on the evoked tritium-outflow was investigated. $N^6-Cyclopentyladenosine$ (CPA), a specific $A_1-adenosine$ receptor agonist, in concentrations Tanging from 0.1 to $10{\mu}M$ decreased the $[^3H]-NE$ release in a dose-dependent mauler without any change of basal rate of release. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, $2{\mu}M$), a selective $A_1-receptor$ antagonist, inhibited the CPA effect. The responses to N-ethylmaleimide $(3&10{\mu}M)$, a SH-alkylating agent of G-protein, were characterized by increments of the evoked NE-release and the CPA effects were completely abolished by NEM pretreatment. Forskolin, a specific adenylate cyclase activator, in concentrations ranging from 0.1 to $30{\mu}M$ increased the evoked and basal rate of NE release in a dose-dependent manner and the CPA effects were inhibited by forskolin pretreatment. Rolipram $(1&10{\mu}M)$, a phosphodiesterase inhibitor, did not affect the evoked NE release but reduced the CPA effect. And 8-bromo-cAMP $(100&300{\mu}M)$, a membrane permeable cAMP analogue inhibited the CPA effect significantly. These results suggest that the $A_1-adenosine$ heteroreceptor plays an important role in NE-release via nucleotide-binding protein $G_i$ in the rat hippocampus and that the adenylate cyclase system might be participated in this process.