• 생명과학회지
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• 제20권6호
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• pp.831-837
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• 2010

KR-31125는 피리딜 이미다졸 시리즈 화합물로서 비펩타이드 안지오텐신 수용체 길항제로 새롭게 개발되었다. 동위원소 리간드를 사용한 재조합 수용체 결합실험과 기능성 토끼혈관실험 결과 기존 의약인 로자탄과 동등수준의 수용체 길항효과를 나타내었다. 이러한 KR-31125의 특징들은 제 1형 안지오텐신 수용체에 특이적으로 나타났으며($IC_{50}$: $19.72{\pm}2.65\;nM$), 표준물질에 대한 대조실험 결과 제 2형 안지오텐신 수용체에 대한 결합친화력은 발견되지 않았다. 기능성 혈관실험에서 KR-31125가 안지오텐신에 의한 혈관수축 효과를 경쟁적으로 저하시켰지만 표준물질인 로자탄과는 달리 농도가 증가함에 따라 30-80% 정도의 최대 수축효과 감소가 관찰되어 로자탄과는 다른 분자작용 기전을 가진다고 판단된다. 제 1형 안지오텐신 수용체에 선택적으로 작용하는 것으로 나타난 KR-31125는 레닌-안지오텐신-알도스테론 시스템에 대한 연구 및 진단에 폭 넓게 활용될 수 있는 표지자 화합물로 가능성을 넓혀 줄 수 있을 것이라고 판단된다.

• The Korean Journal of Physiology and Pharmacology
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• 제11권5호
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• pp.197-206
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• 2007

The aim of the present study was to investigate the effects of 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(SKF81297), a selective agonist of dopaminergic $D_1$ receptor, on the secretion of catecholamines(CA) evoked by cholinergic stimulation and membrane-depolarization in the isolated perfused rat adrenal gland, and also to elucidate the mechanism involved. SKF81297($10{\sim}100{\mu}M$) perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition of CA secretory responses evoked by ACh(5.32 mM), high $K^+$(56 mM), DMPP($100{\mu}M$) and McN-A-343($100{\mu}M$). Also, in adrenal glands loaded with SKF81297($30{\mu}M$), the CA secretory responses evoked by Bay-K-8644($10{\mu}M$), an activator of L-type $Ca^{2+}$ channels and cyclopiazonic acid($10{\mu}M$), an inhibitor of cytoplasmic $Ca^{2+}$-ATPase were also inhibited. However, in the presence of the dopamine $D_1$ receptor antagonist, (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-benzazepine-7-ol(SCH23390, $3{\mu}M$), which is a selective antagonist of dopaminergic $D_1$ receptor, the inhibitory responses of SKF81297($30{\mu}M$) on the CA secretion evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644, and cyclopiazonic acid were significantly reduced. Collectively, these experimental results suggest that SKF81297 inhibits the CA secretion from the rat adrenal medulla evoked by cholinergic stimulation(both nicotininc and muscarinic receptors) and membrane depolarization. This inhibitory of SKF81297 seems to be mediated by stimulation of dopaminergic $D_1$ receptors located on the rat adrenomedullary chromaffin cells, which are relevant to extra- and intracellular calcium mobilization. Therefore, it is thought that the presence of the dopaminergic $D_1$ receptors may be involved in regulation of CA release in the rat adrenal medulla.

• International Journal of Oral Biology
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• 제37권1호
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• pp.1-7
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• 2012

Opioid receptors have been pharmacologically classified as ${\mu}$, ${\delta}$, ${\kappa}$ and ${\varepsilon}$. We have recently reported that the antinociceptive effect of morphine (a ${\mu}$-opioid receptor agonist), but not that of ${\beta}$-endorphin (a novel ${\mu}/{\varepsilon}$-opioid receptor agonist), is attenuated by whole body irradiation (WBI). It is unclear at present whether WBI has differential effects on the antinociceptive effects of ${\mu}-$, ${\delta}-$, ${\kappa}-$ and ${\varepsilon}$-opioid receptor agonists. In our current experiments, male ICR mice were exposed to WBI (5Gy) from a $^{60}Co$ gamma-source and the antinociceptive effects of opioid receptor agonists were assessed two hours later using the hot water ($52^{\circ}C$) tail-immersion test. Morphine and $D-Ala^2$, $N-Me-Phe^4$, Gly-olenkephalin (DAMGO), [$D-Pen^2-D-Pen^5$] enkephalin (DPDPE), trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide (U50,488H), and ${\beta}$-endorphin were tested as agonists for ${\mu}$, ${\delta}$, ${\kappa}$, and ${\varepsilon}$-opioid receptors, respectively. WBI significantly attenuated the antinociceptive effects of morphine and DAMGO, but increased those of ${\beta}$-endorphin. The antinociceptive effects of DPDPE and U50,488H were not affected by WBI. In addition, to more preciously understand the differential effects of WBI on ${\mu}-$ and ${\varepsilon}$-opioid receptor agonists, we assessed pretreatment effects of ${\beta}$-funaltrexamine (${\beta}$-FNA, a ${\mu}$-opioid receptor antagonist) or ${\beta}$-$endorphin_{1-27}$ (${\beta}$-$EP_{1-27}$, an ${\varepsilon}$-opioid receptor antagonist), and found that pretreatment with ${\beta}$-FNA significantly attenuated the antinociceptive effects of morphine and ${\beta}$-endorphin by WBI. ${\beta}$-$EP_{1-27}$ significantly reversed the attenuation of morphine by WBI and significantly attenuated the increased effects of ${\beta}$-endorphin by WBI. The results demonstrate differential sensitivities of opioid receptors to WBI, especially for ${\mu}-$ and ${\varepsilon}$-opioid receptors.

• Journal of Yeungnam Medical Science
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• 제11권2호
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• pp.314-322
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• 1994

개의 기관 평활근에서 GABA수용체의 존재여부를 검정하고, 아울러 GABA와 diazepam의 작용기전을 추정해 보기 위하여 다음과 같은 실험을 하였다. 개의 기관을 절재하여 $4^{\circ}C$의 Tyrode 영양액내에서 폭 2mm 길이 15mm의 수평 근절편으로 만들었다. 기관근 절편은 양끝을 견사로 결찰하여 1 ml의 Tyrode 영양액이 함유되어 있는 적출근편실험조 내에서 등척성 장력을 측정하여 polygraph에 그 수축력을 묘기하였다. 실험조내의 영양액의 온도는 $37^{\circ}C$로 유지시키고, 95%산소와 5% 이산화탄소의 혼합 기체를 공급하여 pH를 7.4로 유지하였다. 실험조 내에 장치된 두개의 백금선 전극을 통하여 전기장자극을 가하고 전기장자극유발 수축에 대한 GABA와 diazepam 및 GABA 수용체 길항제들의 상호작용을 관찰하였다. GABA와 diazepam은 기관지 절편의 수축반응을 같은 양상, 같은 정도로 유의하게 억제하였다. GABA와 Diazepam에 의한 수축억제작용은 $GABA_A$ 수용체 봉쇄제인 bicuculline에 의해서는 유의하게 길항되었으나 $GABA_B$ 수용체 봉쇄제인 ${\delta}$-Aminovaleric acid 에 의해서는 전혀 영향을 받지 않았다. 이상의 결과로 보아 본 실험의 조건하에서 개의기관 평활근에는 $GABA_A$ 수용체가 존재하며, GABA와 diazepam은 말초형의 $GABA_A$ 수용체에 작용하여 콜린성신경지배에 의한 기관근 수축을 억제한다고 사료된다.

• Biomolecules & Therapeutics
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• 제8권2호
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• pp.132-139
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• 2000

This study was performed far investigation of influence on renal function of idazoxan, $\alpha_{2}$-adrenergic antagonist, using the dog. Idazoxan, when giver. into vein, produced the decrease of urine volume(vol) accompanied with the reduction of free water clearance($C_{H2O}$), amounts of sodium excreted in urine($E_{Na}$), with the increase of potassium excreted in urine($E_{K}$), and so ratios of potassium against sodium($K^{+}/Na^{+}$) were elevated, at this time, greatened reabsorption rate of sodium and diministered that of potassium in renal tubules were appeared. Idazoxan administered into a renal artery elicited the augmentation of vol, glomerular filtration rate(GFR), renal plasma flow(RPF) and no change of filtration fraction(FF) in only ipsilateral kidney, whereas $E_{Na},\;E_{K}\;and\;K^{+}/Na^{+}$ were increased and $C_{H2O}$ was decreased in both control and experimental kidney. Idazoxan given into carotid artery showed partial increased vol, remarkable expanded RPF and unchanged GFR, and so filtration fraction(FF) was markedly reduced. Above results suggest that anti- diuretic action of idazoxan given into vein is mediated by reduction of $C_{H2O}\;and\;E_{Na}$, diuretic action only in the ipsilateral kidney by idazoxan given into a renal artery is caused by hemodynamic improvement through expansion of vas afferens in glomeruli.

• The Korean Journal of Physiology and Pharmacology
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• 제4권5호
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• pp.347-353
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• 2000

It has been well documented that a massive release of not only glutamate but also other neurotransmitters may modulate the final responses of nerve cells to the ischemic neuronal injury. But there is no information regarding whether the release of monoamines is directly associated with synaptic vesicular proteins under ischemia. In the present study, it was investigated whether synapsin 1, syntaxin and SNAP-25 are involved in the release of 5-hydroxytryptamine $([^3H]5-HT)$ in glucose/oxygen deprived (GOD) rat hippocampal slices. And, the effect of NMDA receptor using DL-2-amino-5-phosphonovaleric acid (APV) on ischemia- induced release of 5-HT and the changes of the above proteins were also investigated. GOD for 20 minutes enhanced release of $[^3H]5-HT,$ which was in part blocked by the NMDA receptor antagonist, APV. The augmented expression of synapsin 1 during GOD for 20 minutes, which was also in part prevented by APV. In contrast, the expression of syntaxin and SNAP-25 were not altered during GOD. These results suggest that ischemic insult induces release of $[^3H]5-HT$ associated with synapsin 1, synaptic vesicular protein, via activation of NMDA receptor in part.

• The Korean Journal of Pain
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• 제34권1호
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• pp.27-34
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• 2021

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major reason for stopping or changing anticancer therapy. Among the proposed pathomechanisms underlying CIPN, proinflammatory processes have attracted increasing attention. Here we assessed the role of prostaglandin D2 (PGD2) signaling in cisplatin-induced neuropathic pain. Methods: CIPN was induced by intraperitoneal administration of cisplatin 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. PGD2 receptor DP1 and/or DP2 antagonists were administered intrathecally and the paw withdrawal thresholds were measured using von Frey filaments. Spinal expression of DP1, DP2, hematopoietic PGD synthase (H-PGDS), and lipocalin PGD synthase (L-PGDS) proteins were analyzed by western blotting. Results: The DP1 and DP2 antagonist AMG 853 and the selective DP2 antagonist CAY10471, but not the DP1 antagonist MK0524, significantly increased the paw withdrawal threshold compared to vehicle controls (P = 0.004 and P < 0.001, respectively). Western blotting analyses revealed comparable protein expression levels in DP1 and DP2 in the spinal cord. In the CIPN group the protein expression level of L-PGDS, but not of H-PGDS, was significantly increased compared to the control group (P < 0.001). Conclusions: The findings presented here indicate that enhanced PGD2 signaling, via upregulation of L-PGDS in the spinal cord, contributes to mechanical allodynia via DP2 receptors in a cisplatin-induced neuropathic pain model in rats, and that a blockade of DP2 receptor activation may present a novel therapeutic target for managing CIPN.

• Environmental Analysis Health and Toxicology
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• 제9권1_2호
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• pp.9-17
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• 1994

The Ha-antagonist, cimetidine, has been shown to retard the hepatic elimination of low and high clearance drugs, and this has been attributed to inhibition of microsomal cytochrome P-450. This study was done to determine the effects of low (50$\mu\textrm{g}$) and high (1mg) dose of famotidine, another histamine H$_2$-receptor antagonist, on hepatic elimination of propranolol compared with cimetidine in the isolated perfused rat liver. Both low and high dose of cimetidine not only inhibited the elimination of propranolol but also increased the area under the perfusate propranolol concentration time curve (AUC). In contrast, low and high dose of famotidine did not affect hepatic elimination of propranolol. Our findings suggest that famotidine has not a propensity for hepatic microsomal inhibition.

• 약학회지
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• 제32권6호
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• pp.402-414
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• 1988

In order to clarify the receptor types and mechanisms underlying the positive inotropic effect of dopamine on the mammalian ventricular myocardium, the action potential, its first derivatives and isometric contraction of the rabbit papillary muscle were recorded using a force transducer and glass capillary microelectrodes filled with 3M KCl. The results were as follows; (1) In normal Tyrode solution, the contractile force was increased and duration of action potential was shortened with increments of dopamine concentration ($10^{-6}-10^{-4}M$). (2) The dose-response curve was markedly shifted to the right by pretreatment with reserpine (5mg/kg i.p., 24hrs prior to the experiment). (3) In 19mM $K^+-Tyrode$ solution, the duration of action potential, maximum rate of rise (V_{max}) of action potential and overshoot were significantly increased with increments of dopamine concentration ($10^{-6}-10^{-4}M$). (4) The inotropic effect of dopamine on the rabbit papillary muscle pretreated with reserpine was antagonized by atenolol ($10^{-6}M$), but not by phentolamine ($3{\times}10^{-6}M$). (5) In rabbit papillary muscle partially depolarized by 19mM $K^+-Tyrode$ solution, slow electrical response (calcium mediated action potential) as well as contraction were restored by dopamine ($10^{-4}M$); this restoration was blocked by calcium antagonists ($3{\times}10^{-5}M$ $LaCl_3{\cdot}6H_2O$, $3{\times}10^{-6}M$ diltiazem) or ${\beta}-adrenoceptor$ antagonist ($3{\times}10^{-6}M$ atenolol), but not affected by ${\alpha}-adrenoceptor$ antagonist ($10^{-5}M$ phentolamine, $3{\times}10^{-6}M$ yohimbine) or vascular dopaminergic receptor antagonist ($10^{-5}M$ haloperidol). The above results may be interpreted as that the positive inotropic effect of dopamine through both direct and indirect action are caused by increase in slow inward current ($Ca^{2+}$ influx into themyocardial cell), and the direct action is mainly due to the stimulation of ${\beta}-adrenoceptors$ in the rabbit papillary muscle.

• Journal of Gastric Cancer
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• 제6권3호
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• pp.132-138
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• 2006

목적: 도파민은 중추신경전달물질이지만 위장관에서 도파민수용체와 결합하여 점막상피세포 증식, 상피세포의 보호, 위암 세포증식과 관련이 있는 것으로 알려져 있다. 본 연구에서는 위암에서 기원한 세포주를 이용하여 도파민과 각각의 도파민 수용체가 위암 세포 증식과 억제에 작용하는 역할에 대해 알아보았다. 대상 및 방법: 위암세포기원에서 각각 유래한 세포주인 SNU601과 KCU-C2를 이용하여 RNA 추출 후 RT-PCR 시행 후 도파민수용체 D1, D2L과 D2S 각각에 대한 primer로 PCR을 시행하여 수용체 유전자의 상대적인 발현정도를 측정하였다. 도파민과 Dl 수용체의 대항제인 SCH 23390과 D2 수용체 대항제인 raclopride를 사용하여 약물처리에 따른 위암세포주에서 세포 증식에 대한 분석을 하였다. 결과: KCU-C2 세포주에서 D1과 D2L과 D2S 유전자 mRNA의 상대적인 발현정도는 모두 높은 발현을 보였지만, SNU 601 세포주에는 mRNA의 발현이 모두 낮은 수준이었으며, 특히 D2L mRNA는 발현되고 있지 않았다. 약물처리에 따른 위암세포주에서 세포증식에 대한 분석에서는 D1과 D2S 수용체를 통한 도파민의 신호는 세포의 증식을 억제하였고 D2L 수용체를 통한 도파민의 신호는 세포의 증식을 유도하였다. 결론: 본 연구를 통해 도파민이 위암의 세포증식과 억제에 관여하며, 도파민의 이러한 효과는 도파민의 신호가 어느 수용체를 통해 전달되었느냐에 따라 위암세포의 증식과 억제가 이루어짐을 알 수 있었다.