• 약학회지
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• 제58권1호
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• pp.16-20
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• 2014

KR-31064 was developed for the strong angiotensin II receptor antagonist among the one of pyridyl imidazol series compounds. To investigate the receptor-ligand binding characteristics of this nonpeptide antagonist, binding experiments were deployed in various conditions and ex vivo contractile responses were tested toward the standard compound, losartan. Receptor binding experiments with radiolabeled angiotensin II, the $IC_{50}$ value for KR-31064 resulted 0.67 nM without any activities toward type 2 angiotensin II receptor. The comparative potency against losartan was more than 18 fold and the specific activity in type 1 angiotensin II receptor was more than 10,000 fold comparing to the type 2 receptor. Scatchard analysis of saturation binding data showed KR-31064 acted on the receptor in a competitive mode. KR-31064 inhibited the contractile response derived by angiotensin II ($pK_B$: 9.86) similar to that of losartan with decreased maximum signals. As a potent and specific type 1 angiotensin II receptor antagonist, KR-31064 may have possibilities for the development of diagnostic ligands that can be used as tools for various biochemical research experiments and non-invasive diagnostics.

• The Korean Journal of Physiology and Pharmacology
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• 제13권5호
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• pp.385-392
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• 2009

Angiotensin II (Ang II) plays an important role in vascular hypertension. The role of the chemokine CCL5 on Ang II-induced activities in vascular smooth muscle cells (VSMCs) has not been studied. In this study, we elucidated the effect of CCL5 on Ang II-induced 12-lipoxygenase (LO) expression and cell proliferation in spontaneously hypertensive rats (SHR) VSMCs. CCL5 decreased Ang II-induced 12-LO mRNA expression and protein production, and it increased Ang II type 2 ($AT_2$) receptor expression in SHR VSMCs. The inhibitory effect of CCL5 on Ang II-induced 12-LO mRNA expression was mediated through the $AT_2$ receptor. Although treatment of CCL5 alone induced SHR VSMCs proliferation, CCL5 inhibited Ang II-induced VSMCs proliferation and PD123,319, an $AT_2$ receptor antagonist, blocked the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation. Phosphorylation of p38 was detected in VSMCs treated with Ang II or CCL5 alone. But, decrease of p38 phosphorylation was detected in VSMCs treated with Ang II and CCL5 simultaneously (Ang II/CCL5) and PD123,319 increased p38 phosphorylation in VSMCs treated with Ang II/CCL5. Therefore, these results suggest that the inhibitory effect of CCL5 on Ang II-induced VSMCs proliferation is mediated by the $AT_2$ receptor via p38 inactivation, and CCL5 may play a beneficial role in Ang II-induced vascular hypertension.

• Journal of Animal Science and Technology
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• 제50권5호
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• pp.649-656
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• 2008

본 연구는 insulin-like growth factors(IGFs)가 돼지 지방전구세포의 증식과 분화에 미치는 작용기전을 구명하기 위해서 수행하였다. 지방전구세포는 갓난 암퇘지의 등지방에서 분리하였고, serum-deprived 조건하에서 IGFs와 mutant IGFs를 함유시켜 배양했는데 이 mutant IGFs는 IGF-Ⅰ에 비해 type-1 IGF receptor와 insulin receptor에 대한 친화력이 낮다. 50ng/ml의 IGF-Ⅰ, [Leu60]IGF-I, IGF-Ⅱ 및 [Leu27]IGF-Ⅱ를 배양중인 세포에 4일동안 처리했다. IGF-Ⅰ, [Leu60]IGF-I, IGF-Ⅱ 및 [Leu27]IGF-Ⅱ는 돼지 지방전구세포의 증식을 각각 39%, 8%, 25% 및 2% 촉진했다(증가된 세포수에 의해 측정). 이 사실은 IGF-Ⅰ과 IGF-Ⅱ는 type-1 IGF receptor 또는 insulin receptor에 결합을 통해서 지방세포의 증식 촉진을 가져왔음을 나타낸다. 그리고 IGF-Ⅰ, [Leu60]IGF-I, IGF-Ⅱ 및 [Leu27] IGF-Ⅱ는 지방전구세포의 분화를 50%, 17%, 37% 및 30% 각각 촉진시켰다(세포 분화는 glycerol- phosphate dehydrogenase 활성도에 의해 측정했다). IGF-Ⅰ의 type-1 IGF receptor 또는 insulin receptor에의 친화력이 낮아져서 세포 분화 촉진작용을 감소시킨 것이다. 그러나 [Leu27] IGF-Ⅱ의 분화촉진 작용은 IGF-Ⅱ의 그것에 비해 크게 차이가 나지 않았는데, 이 사실은 IGF-Ⅰ과 IGF-Ⅱ는 서로 다른 수용체－매개 작용기전에 의해 세포분화를 촉진시킴을 나타낸다. 즉 IGF-Ⅱ는 type-1 IGF receptor 또는 insulin receptor가 관여하지 않는 작용을 통해 돼지 지방전구세포의 분화를 촉진시켰다. 이 작용은 IGF-Ⅱ가 type-2 IGF receptor(또는 cation- independent mannose-6 phosphate receptor [CIM6P /IGF2 receptor])에 결합을 통해서 이뤄지는 것으로 여겨진다. 위의 결과는 IGF-Ⅱ가 CIM6P/ IGF2 receptor에의 결합을 통해 동물 지방전구세포의 분화를 촉진시킨다는 것을 밝혀낸 최초의 연구이다. 요약하면 이 본 연구는 IGF-Ⅰ과 IGF-Ⅱ는 서로 다른 세포내 receptor가 관여하는 작용기전을 통해 돼지 지방전구세포의 분화를 촉진함을 보여준다.

• The Korean Journal of Physiology and Pharmacology
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• 제3권3호
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• pp.315-320
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• 1999

Molecular regulation of the renin-angiotensin system (RAS) was investigated in deoxycorticosterone acetate (DOCA)-salt hypertension. The expression of renin, angiotensinogen and angiotensin II receptor genes in the kidney and liver was determined by Northern blot analysis in rats which were made DOCA-salt hypertensive over the period of 2 or 4 weeks. Along with the hypertension, renin mRNA was decreased in the remnant kidney. The expression of angiotensinogen gene was not significantly altered in the kidney, but was significantly decreased in the liver. The expression of angiotensin II receptor gene was increased in the kidney, while it remained unaltered in the liver. The duration of hypertension did not affect the altered gene expression. It is suggested that the components of RAS are transcriptionally regulated in DOCA-salt hypertension in a tissue-specific manner.

• Molecules and Cells
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• 제20권2호
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• pp.263-270
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• 2005

Transactivation of EGF-receptor (EGFR) by G-protein coupled receptors (GPCRs) is emerging as an important pathway in cell proliferation, which plays a crucial role in the development of atherosclerotic lesion. Angiotensin II (Ang II) has been identified to have a major role in the formation of atherosclerotic lesions, although the underlying mechanisms remain largely unclear. We hypothesize that Ang II promotes the proliferation and migration of smooth muscle cells through the release of heparin-binding epidermal growth factor like growth factor (HB-EGF), transactivation of EGFR and activation of Akt and Erk 1/2, with matrix metalloproteases (MMPs) playing a dispensable role. Primary rat aortic smooth muscle cells were used in this study. Smooth muscle cells rendered quiescent by serum deprivation for 12 h were treated with Ang II (100 nM) in the presence of either GM6001 ($20{\mu}M$), a specific inhibitor of MMPs or AG1478 ($10{\mu}M$), an inhibitor of EGFR. The levels of phosphorylation of EGFR, Akt and Erk 1/2 were assessed in the cell lysates. Inhibition of MMPs by GM6001 significantly attenuated Ang II-stimulated phosphorylation of EGFR, suggesting that MMPs may be involved in the transactivation of EGFR by Ang II receptor. Furthermore Ang II-stimulated proliferation and migration of smooth muscle cells were significantly blunted by inhibiting MMPs and EGFR and applying HB-EGF neutralization antibody, indicating that MMPs, HB-EGF and EGFR activation is necessary for Ang-II stimulated migration and proliferation of smooth muscle cells. Our results suggest that inhibition of MMPs may represent one of the strategies to counter the mitogenic and motogenic effects of Ang II on smooth muscle cells and thereby prevent the formation and development of atherosclerotic lesions.

• 한국산학기술학회논문지
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• 제10권10호
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• pp.2997-3003
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• 2009

비펩타이드성 안지오텐신 수용체 길항제로 새롭게 개발된 KR-31081은 재조합 수용체 결합실험에서 기존 의약인 로사탄에 비하여 8.6배 이상의 월등한 효과를 나타내었으며, 기능성 혈관실험에서도 대조물질인 로자탄보다 혈관수축 억제효과가 10배 이상 탁월하였다. 이러한 KR-31081의 특징들은 제 1형의 안지오텐신 수용체에 특이적으로 나타났으며 제 2형의 안지오텐신 수용체에 대한 수용체 결합친화력이 발견되지 않았다. 기능성 혈관실험에서는 KR-31081이 안지오텐신에 의한 혈관수축 효과를 경쟁적으로 저하시켰지만 표준물질인 로자탄과는 달리 농도가 증가함에 따라 혈관자체의 최고 수축효과의 감소가 관찰되었다. 안지오텐신 수용체에 선택적으로 작용하는 것으로 나타난 KR-31081은 고혈압 및 혈관질환에 대한 연구 및 진단에 활용될 수 있을 것이라고 판단된다.

• 한국생물물리학회:학술대회논문집
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• 한국생물물리학회 1996년도 정기총회 및 학술발표회
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• pp.23-23
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• 1996

A working molecular model of the angiotensin II type 1 receptor is built based on the seven transmembrane helix structure of the recently refined bacteriorhodopsin atomic coordinates. A multiple copy simultaneous search (MCSS) method is used to search the pharmacophore of angiotensin on the surface of the receptor. Multiple copies of amino acid fragments and organic functional groups are scattered around the possible binding site and the time dependent. (omitted)

• Archives of Pharmacal Research
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• 제18권3호
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• pp.215-216
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• 1995

• Tuberculosis and Respiratory Diseases
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• 제55권5호
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• pp.478-487
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• 2003

연구배경 : Angiotensin II가 폐포상피세포의 세포사멸을 유도하고 폐섬유모세포에서 TGF-${\beta}$등의 발현을 증가시켜 폐섬유화증을 촉진시킬 수 있다고 알려져 있어 angiotensin II receptor의 차단이 폐섬유화증을 감소시키는 효과가 있을 것으로 예상하고 특발성 폐섬유화증 환자에게 angiotensin II receptor antagonist(AGIIRA)를 투여하여 치료효과를 알아보고자 하였다. 방 법 : 저자들은 가천의대 길병원에서 특발성 폐섬유화증으로 진단된 13명의 환자를 대상으로 하였다. 이들 중 8명 의 환자에게는 angiotensin II type 1 receptor antaginist인 losartan(cozaar$^{(R)}$) 을 투여하였고 나머지 5명의 환자에게는 losartan을 투여 하지 않았으며, 치료 직전과 치료 l년 후에 모든 환자에게 폐기능 검사와 호흡곤란 지수의 정도의 변화를 측정하여 그 결과를 비교하였다. 결 과 : AGIIRA 복용 군에서는 폐기능이 전체적으로 약간의 호전을 보였으며, 미 복용 군에서는 DLco%가 5%로 증가하였으나 TLC가 14%로 감소하는 등 전반적으로 페기능이 감소하는 소견을 보였다. 폐기능 변화가 두 군 모두 통계적으로 유의성이 없었고 두 군간의 변화율의 변화에서도 통계적 유의성은 없었다. 호흡곤란 지수는 AGIIRA 복용한 군에서만 통계적으로 유의하게 더 호전을 보였다. 결 론 : 특발성 폐섬유화증의 치료에 AGIIRA가 일부 환자들에게 임상적 안정화에 도움을 줄 수 있을 것으로 사료된다. 차후 더 많은 환자를 대상으로 오랜 기간의 연구와 함께 폐섬유화에 있어서 anglotensin II와 그 receptor에 대한 기전과 역할에 대하여 더 많은 연구가 필요할 것으로 생각된다.

• 약학회지
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• 제28권6호
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• pp.305-311
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• 1984

Relationship between hypertension and monoamine oxidase (MAO) activity in rat brain and the change of this relationship by presynaptic ${\alpha}-receptor$ agonist were studied. Animals were divided into three groups. Group I was composed of normotensive Sprague-Dawley rats (NR), group II of spontaneously hypertensive rats (SHR) and group III of acquired hypertensive rats induced by deoxycorticosterone acetate (DOCA) and NaCl treatment. Clonidine, a presynaptic ${\alpha}-receptor$ agonist, was administered to groups II and III. Blood pressures and MAO activities were measured in each group. MAO activities in the brain of SHR were lower than those of NR. Animals in group II received clonidine which lowered blood pressures but did not change MAO activities in the brain. DOCA and NaCl induced hypertension 21 days after these treatments in group III and did not cause any changes in brain MAO activity. Clonidine lowered blood pressures of group III but did not change MAO activities. The data from the present study suggest that abnormaly low MAO activities in SHR brain may be one of the underlying factors for the susceptibility to hypertension and that the decrease in noradrenergic neuronal activities through presynaptic ${\alpha}-receptor$ activation by clonidine may not be related to the changes of brain MAO activities.