• Biomolecules & Therapeutics
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• 제16권4호
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• pp.320-327
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• 2008

Several lines of evidence indicate that adenosine $A_{2A}$ agonist disrupts spatial working memory. However, it is unclear which stages of learning and memory are affected by the stimulation of adenosine $A_{2A}$ receptor. To clarify these points, we employed CV-1808 as adenosine $A_{2A}$ agonist and investigated its effects on acquisition, consolidation, and retrieval phases of learning and memory using passive avoidance and the Morris water maze tasks. During the acquisition phase, CV-1808 (2-phenylaminoadenosine, 1 and 2 mg/kg, i.p.) decreased the latency time in passive avoidance task and the mean savings in the Morris water maze task, respectively. During the consolidation and retrieval phase tests, CV-1808 did not exhibited any effects on latency time in passive avoidance task and the mean savings in the Morris water maze task. These results suggest that CV-1808 as an adenosine $A_{2A}$ agonist impairs memory acquisition but not consolidation or retrieval.

• Bulletin of the Korean Chemical Society
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• 제28권4호
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• pp.561-566
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• 2007

Adenosine kinase (AK) is a ubiquitous intracellular enzyme, which catalyzes the phosphorylation of adenosine (ADO) to adenosine monophosphate (AMP). AK inhibitors have therapeutic potential as analgesic and antiinflammatory agents. A chemical feature based pharmacophore model has been generated from known AK inhibitors (26 training set compounds) by HypoGen module implemented in CATALYST software. The top ranked hypothesis (Hypo1) contained four features of two hydrogen-bond acceptors (HBA) and two hydrophobic aromatics (Z). Hypo1 was validated by 124 test set molecules with a correlation coefficient of 0.905 between experimental and estimated activity. It was also validated by CatScramble method. Thus, the Hypo1 was exploited for searching new lead compounds over 238,819 chemical compounds in NCI database and then the selected compounds were screened based on restriction estimated activity and Lipinski's rules to evaluate their drug-like properties. Finally we could obtain 72 new lead candidates and the two best compound structures from them were posted.

• 한국미생물·생명공학회지
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• 제21권1호
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• pp.23-29
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• 1993

토양으로부터 nucleoside oxidase 생산균주를 분리하고 Flavobacterium meningosepticum으로 동정하였다. 생산균주의 cell free extract로부터 본 효소를 정제배율 180배, 수율 18로 전기영동적으로 균일하게 정제하였으며 정제효소의 기질 특이성을 검토한 결과 nucleoside만을 산화시키는 전형적인 nucleoside oxidase이었다. Adenosine을 기질로 한 표준효소반응계에서 stoichiometry를 검토한 결과 본 효소는 lmol adenosine을 중간 생성물인 adenosice 5'-aldeh-yde로 산화 후 1 mol adenosine 5'-carboxylic acid까지 2단계로 산화시키면서 동시에 2 mol H2O2를 생성하는 새로운 type의 nucleoside oxidase로 확인되었다. 본 효소의 높은 기질 특이성과 H2O2를 생성하는 반응성은 nucleoside의 신속 간편한 효소학적정량볍 및 임상진단용 시약의 개발에 응용될 수 있음을 시사하였다.

• 대한핵의학회지
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• 제26권1호
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• pp.72-81
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• 1992

Pharmacologic coronary vasodilation in conjunction with myocardial scintigraphy has become an accepted alternative to dynamic exercise testing for the diagnosis of coronary artery disease. Although dipyridamole has traditionally been used for this purpose, it causes frequent side effect, which at times can be life-threatening. Moreover, dipyridamole dose not elicit maximal coronary vasodilation in a substantial number of patients receiving the usual i.v. dose. Adenosine is an endogenously produced compound that has significant effects as a coronary vasodilator and rapid onset action and extremely short half-life (< 10 seconds). The diagnostic accuracy and safety profile of adenosine $^{99m}Tc-MIBI$ myocardial scintigraphy were evaluated and comparison with exercise $^{99m}Tc-MIBI$ was performed. Twenty-eight subjects underwent $^{99m}Tc-MIBI$ imaging after adenosine infusion and exercise $^{99m}Tc-MIBI$ imaging. Adenosine was infused intravenously at a dose of 0.14mg/kg/body weight per minute for 6 min and MIBI was injected at 3 minute. Adenosine caused an incerease in heart rate ($64{\pm}12$ at baseline versus $74{\pm}16$ beats/min at peak effect, p<0.001), a mild decrease in systolic and diastolic blood pressure and a slightly increase in PR interval(p; NS). Side effects were reported in 92% of patients and were mostly mild in nature and promptly resolved within 1 or 2 minutes of termination of adenosine infusion. Facial flushing (53%), chest pain (36%), mild dyspnea (39%), headache (21%), throat discomfort (21%) were frequent symptoms. ST segment depression (> 1 mm) and second degree AV block in electrocardiography occured in 11% of the patients, respectively. The overall sensitivity and specificity for individual coronary stenoses in 16 patients underwent coronary angiography were 88% and 95%, respectively. The agreement ratio of segmental perfusion between adenosine and exercise images was 92% (Kappa index=0.82). In conclusion, $^{99m}Tc-MIBI$ myocardial perfusion scintigraphy with intravenous adenosine is a feasible, safe and highly accurate noninvasive technique for the detection of coronary artery disease and results are at least comparable with those of exercise $^{99m}Tc-MIBI$ scintigraphy.

• The Korean Journal of Physiology
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• 제21권2호
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• pp.225-239
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• 1987

The effects of adenosine on the mechanical contractions and electrical activities were investigated in guinea-pig stomach. Spontaneous contractions of the antral region were recorded with force transducer, and the phasic contractions of fundic region were induced by electrical field stimulation. Electrical responses of smocth muscle cells were recored using glass capillary microelectrodes filled with 3M-KCl. Field stimulation was applied transmurally by using a pair of platinum wire (0.5 mm in diameter) placed on both sides of tissue. All experiments were performed in tris-buffered Tyrode solution which was aerated with 100% $O_2$ and kept at $35^{\circ}C$. The results obtained were as follows. 1) Adenosine suppressed the spontaneous contractions of antrum in a dose-dependent manner. 2) The inhibitory effect on antral spontaneous contractions was not influenced by the administration of guanethidine $(5{\times}10^{-6}\;M)$ and atropine $10^{-6}\;M$, or in the presence of dipyridamole $10^{-7}\;M$. 3) The phasic contractions of fundus induced by electrical field stimulation, which disappeared rapidly by the addition of tetrodotoxin $(3{\times}10^{-7}\;M)$, were potentiated by adenosine in the presence of guanethidine. 4) Adenosine decreased the amplitude and the maximum rate of rise of slow waves, and the increased amplitude and rate of rise evoked in the high calcium solution or in the presence of TEA were decreased by adenosine. 5) The non-adrenergic, non-cholinergic inhibitory junction potential (IJP) was inhibited by adenosine in the antral region, while the excitatory junction potential (EJP) in the fundic region was potentiated. From the above results, the following conclusions could be made. 1) Adenosine suppresses the spontaneous contractions of antrum strip by the decrease in amplitude and rate of rise of slow waves. 2) The release of neurotransmitter(s) from non-adrenergic, non-cholinergic nerve terminals is inhibited by adenosine.

• The Korean Journal of Physiology
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• 제22권2호
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• pp.319-332
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• 1988

The regulations of renal function and renin release are influenced by neural, humoral and physical factors. During the last decade, considerable progress has been made in the identification and characterization of these extrinsic renal control systems. Mechanisms intrinsic to the kidney are also important for renal function. These include the autoregulation of blood flow, and the local control of renin secretion. Fundamental questions regarding the mechanism of these intrinsic controls remain unanswered. Recently, endogenous renal adenosine has been claimed to influence the tubuloglomerular feedback control and renin release. Two subclasses of adenosine receptors $A_1{\;}and{\;}A_2$ have been described. The present experiment was carried out to evaluate the effects of $N_6-cyclohexyladenosine$ $(CHA,{\;}A_1{\;}selective)$ and 5'-N-ethylcarbox-amide adenosine $(NECA,{\;}A_2{\;}selective)$ on the renal function and renin release in the unanesthetized rabbit. Intra-renal arterial infusion of NECA $(0.3{\sim}10.0n{\;}mole/min/rabbit)$ or CHA $(0.03{\sim}10.0n{\;}mole/min/rabbit)$ caused a prompt and dose-dependent decrease in urine volume, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction (FF), electrolyte excretion and free water clearance $(CH_2O)$, the effect being much more profound with CHA than with NECA. The NECA infusion resulted in a profound decrease of systemic blood pressure, but the CHA infusion did not. Both NECA and GHA infusions caused a prompt and dose-dependent decrease in renin secretion rate, again the effect being greater with CHA than with NEGA. These results suggest that both $A_1{\;}and{\;}A_2$ adenosine receptors may be involved in the intrinsic control of renal function and renin release, and that the $A_1$ receptors plays a more important role than the $A_2$ receptor in the regulation of renal fnction.

• The Korean Journal of Physiology and Pharmacology
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• 제1권1호
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• pp.1-12
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• 1997

As it has been reported that the depolarization induced acetylcholine (ACh) release is modulated by activation of presynaptic $A_1$ adenosine heteroreceptor and various evidence suggest that indicate the $A_2$ adenosine receptor is present in the striatum, this study was undertaken to delineate the role of adenosine receptors on the striatal ACh release. Slices from the rat striatum were equilibrated with $[^3H]$choline and then the release amount of the labelled product, $[^3H]$ACh, which was evoked by electrical stimulation (rectangular pulses, 3 Hz, 2 ms, 24 mA, $5\;Vcm^{-1}$, 2 min), was measured, and the influence of various agents on the evoked tritium outflow was investigated. And also, quantitative receptor autoradiography and drug-receptor binding assay were performed in order to confirm the presence and characteristics of $A_1$ and $A_2$ adenosine receptors in the rat striatum. Adenosine $(10{sim}100\;{mu}M)$ and $N^6$-cyclopentyladenosine (CPA, $1{sim}100\;{mu}M)$ decreased the $[^3H]$ACh release in a dose-dependent manner without changing the basal rate of release in the rat striatum. The reducing effects of ACh release by adenosine and CPA were abolished by 8-cyclopentyl-1,3-dipropy-Ixanthine (DPCPX, 2 ${mu}M$), a selective $A_1$, adenosine receptor antagonist, treatment. The effect of adenosine was potentiated markedly by 3,7-dimethyl-1-propargylxanthine (DMPX, 10 ${mu}M$), a specific $A_2$ adenosine receptor antagonist. 2-P-(2-carboxyethyl)phenethylamimo-5'-N- ethylcarboxamidoadenosine hydrochloride (CGS-21680C), in concentrations ranging from 0.01 to 10 ${mu}M$, a recently introduced potent $A_2$ adenosine receptor agonist, increased the $[^3H]$ACh release in a dose related fashion without changing the basal rate of release. These effects were completely abolished by DMPX $(10\;{mu}M)$. In autoradiograrhy experiments, $[^3H]$2-chloro-$N^6$-cyclopentyladenosine ($[^3H]$ CCPA) bindings were highly localized in the hippocampus and the cerebral cortex. Additionally, lower levels of binding were found in the striatum. However, $[^3H]$CGS-21680C bindings were highly localized in the striatal region with the greatest density of binding found in the caudate nucleus and putamen. Lower levels of binding were also found in the nucleus accumbens and olfactory tubercle. In drug-receptor binding assay, binding of $[^3H]$ CCPA to $A_1$ adenosine receptors of rat striatal membranes was inhibited by CPA ($K_i$ = 1.6 nM) and N-ethylcarboxamidoadenosine (NECA, $K_i$ = 12.9 nM), but not by CGS-21680C ($K_i$ = 2609.2 nM) and DMPX ($K_i$ = 19,386 nM). In contrast, $[^3H]$CGS-21680C binding to $A_2$ denosine receptors was inhibited by CGS-21680C ($K_i$ = 47.6 nM) and NECA ($K_i$ = 44.9 nM), but not by CPA ($K_i$ = 2099.2 nM) and DPCPX ($K_i$ = 19,207 nM). The results presented here suggest that both types of $A_1$ and $A_2$ adenosine heteroreceptors exist and play an important role in ACh release in the rat striatal cholinergic neurons.

• Journal of Chest Surgery
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• 제31권9호
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• pp.837-844
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• 1998

배경: 아데노신은 심근의 허혈상태에서 심근세포로부터 분비되어 부정맥과 심근허혈 및 수술후 재관류손상을 억제시키는 호르몬으로 알려져 있다. 아데노신의 심근보호 효과에 대한 연구는 주로 심정지액 속에 포함시킨 아데노신의 효과에 대하여 이루어 지고 있으나, 심정지액 속에 포함된 아데노신의 적정용량에 대해서는 보고가 다양하다. 저자들은 자체제작한 심폐체외순환 모델을 이용하여 단일용량의 아데노신(0.75 mg/Kg/min)이 우수한 심근보호효과를 나타낸 결과를 보고한 바 있으나 적절한 용량이었는지에 대한 확신은 없다. 따라서 본 연구의 목적은 심정지액 속에 포함된 아데노신의 적정용량을 알아보는데 있다. 대상 및 방법: 연구방법은 쥐를 이용하여 심정지시 심정지액(St. Thomas 심정지액)에 첨가한 아데노신의 용량에 따라 1군(0.5 mg/Kg/min), 2군(0.75 mg/Kg/min) 및 3군(1 mg/Kg/min) 으로 나누어 각각 10마리씩 실험하여 비교하였다. 마취 후 적출된 쥐심장의 대동맥과 좌심방에 도관을 삽관한 후에 심폐체외순환 모델에 연결하여 비작업성 순환과 작업성 순환을 시행하면서 혈역학적 수치를 측정하여 이를 대조값으로 이용하였다. 심정지액을 주입하여 심정지를 유도한 후에 90분간 허혈상태로 유지한 다음 비작업성 순환을 시행 후 작업성 순환으로 바꿔 10분, 30분 및 60분에 혈역학적 수치(심박동수, 수축기 대동맥압, 1분간 대동맥 박출량 및 관동맥관류량)를 측정하고, 생화학적 검사(CPK, Lactic Acid) 및 심장의 수분함유량도 측정하였다. 측정된 수치는 심정지 전 측정한 대조값에 대한 백분율로 환산하여 비교하였다. 결과: 실험 결과 심정지 전에 측정한 대조값 사이에는 세군 사이의 통계적인 유의성이 없었다. 심정지액의 주입 후 3군에서 가장 빨리 심정지가 일어났으며(p<0.05), 재관류 후 심박동이 돌아온 시간은 1군과 2군이 3군에 비하여 통계학적으로 유의하게 심박동이 빨리 돌아 왔다 (p<0.05). 그러나 1군과 2군 사이에는 유의성이 없었다. 심장의 재관류 후 측정한 심박동수의 회복률에서 10분에 측정한 값은 세군 사이에 유의성이 없었으나, 30분과 60분 에 측정한 값은 1군이 2군과 3군에 비하여 유의하게 높았으며(p<0.05), 2군도 3군에 비하여 유의하게 높았다(p<0.05). 수축기 대동맥압의 회복률, 1분 동안의 대동맥 박출량 및 심박출량(1분 동안의 대동맥 박출량과 관동맥관류량을 합산한 값)은 10분, 30분 및 60분에서 모두 2군이 1군과 3군에 비하여, 1군은 3군에 비하여 유의하게 높았다(p<0.05). 관동맥관류량의 회복률은 10분과 30분에 측정한 값은 2군이 1군과 3군에 비하여, 1군은 3군에 비하여 유의하게 높았으며(p<0.05), 60분에 측정한 값은 1군과 2군이 3군에 비하여 유의하게 높았다(p<0.05). 심근의 수분함유량과 관상동맥 관류량의 생화학적 검사결과 CPK와 Lactic Acid는 세군 사이에 유의성이 없었다. 결론 : 이상의 결과로 아데노신을 심정지용액에 첨가시 비교적 적정 용량은 0.75 mg/Kg/min 을 투여하는 것이 적절할 것으로 생각된다.

• 대한약리학회지
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• 제19권2호
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• pp.25-34
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• 1983

가토의 문맥 절편에서 비 코린성-비 아드레나린성 이완반응에 대한 약리학적 성질을 규명하여 다음과 같은 결과를 얻었다. 1) 가토 문맥 절편에 있어서 비 코린성-비 아드레나린성 전기자극반응은 자극빈도의 증가에 따라 예민하게 증가하였으며, $Ca^{++}$에 이하여 크게 영향을 받았고, $Ca^{++}$농도를 달리하고 ATP를 첨가하여 이완반응은 일어났으나 이는 전극자극에 의한 반응에는 영향을 주지 아니하였다. 2) ATP, ADT 및 adenosine에 대한 반응은 용량에 의존하여 이완반응은 보였으나 자극에 의한 반응에는 크게 영향을 미치지 아니하였다. 3) Quinine과 isobutyl-methyl xanthine을 투여하였을 때 용량에 따라 긴장도의 하강을 나타내었을 뿐 이완반응은 길항하지 아니하였다. 4) 4-AP, $1{\mu}g/ml$존재하에서 전기자극에 대한 이완반응 폭은 서서히 증가하였고 대량의 4-AP에 의하여 는 긴장도가 하강하였다. 5) 4-AP반복투여후의 전기자극에 이한 반응은 대조군과 비교하여 큰 변화가 없었으나, adenosine을 반복투여하였을 때는 대조군에 비하여 증가를 나타내었다. 6) $^3H-purine$의 유출은 전기자극에 의하여는 경미하나 ATP나 adenosine투여로 현저히 증가하였으며, 4-AP, TTX 및 adenosine 반복투여후에도 $^3H-efflux$의 변동을 나타내지 아니하였다.

• 대한약리학회지
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• 제32권1호
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• pp.31-37
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• 1996

허혈전처치(IP)의 히혈-재관류손상에 대한 심근 보호작용의 기전을 규명하기 위한 일환으로 denosine에 의한 PKC자극이 허혈전처치의 주요 기전으로 작용할 가능성을 조사하였다. 흰쥐 적출심장의 Langendorff 관류 표본에서 실험적인 허혈(30분)-재관류(20분)손상을 유도하였고, 허혈전처치는 허혈-재관류 손상 유도 전에 5분 허혈-5분 재관류를 3회 반복하여 시행하였다. 심근 손상의 지표로 심수축기능, 세포질효소 유출을 측정하였다. Adenosine이 허혈전처치의 심보호 효과에 관여하는지를 관찰하기 위하여 adenosine수용체 억제제인 8-(p-sulfophenyl)-theophylline(SPT), Xanthine amine congener(XAC) 및 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)을 허혈전처치 유도 전에 투여하였다. 또한 PKC가 허혈전처치의 세포내 매개인자로 관여 할 가능성을 관찰하기 위하여 PKC활성 억제제인 polymyxin B 및 chelerythrine과 PKC translocation 억제제인 colchicine을 허혈전처치 유도 전에 투여하였다. 연구성적은 다음과 같다. 1) 허혈전처치는 허혈재관류 심장의 심기능의 저하를 현저히 회복시켜 심기능 회복률은 75%에 달하였다. 2) 허혈-재관류 심장에서 lactate dehydrogenase유출증가는 허혈전처치에 의해 현저히 저하되었다. 3) Adenosine 비선택적 차단제인 SPT와 Al 선택적 차단제인 DPCPX 및 XAC의 투여가 허혈전처치에 의한 심기능회복 및 LDH 유출 감소에 영향을 미치지 않았다. 4) PKC활성 억제제인 polymyxin B 와 chelerythrine을 처치시 히혈전처치 심장의 심기능 회복률이 현저히 감소되었으며 LHD 유출 역시 대조군 심장의 수준으로 증가하였다. 5) PKC translocation을 방해하는 colchicine도 허혈전처치의 심보호 효과를 억제시켰다. 이상의 결과들로부터 adenosine은 흰쥐 심장에서 허혈전처치의 심보호효과에 중요한 세포외 매개물질로 작용할 가능성이 희박하며, PKC는 흰쥐 심장에서 허혈전처치시 세포내 매개 인자로 관여하여 허혈전처치에 의한 심보호효과에 중요한 역할을 할 수 있으리라 사료된다.