• Natural Product Sciences
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• 제26권4호
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• pp.345-350
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• 2020

In recent years, tyrosine kinases (TKs) have been the target to combat cancers, and most of the developed inhibitors are of synthetic origin. Natural compounds that have the properties as the TK's inhibitors are very limited. This paper described the isolation of a new dammarane triterpene from the tree bark of Sandoricum koetjape, along with three known related dammaranes from the damar resin of Shorea javanica, as well as their inhibitory properties against eight receptor TKs (RTKs: EGFR, HER2, HER4, IGF1R, InsR, KDR, PDGFRα, and PDGFRβ). Based on the NMR and mass spectral data the new compound was identified as (12β,20S)-12,20-dihydroxy-3,4-seco-dammaran-4,24-dien-3-oic acid (12β-hydroxydammarenolic acid) (1), while the three known compounds were identified as (20S)-20-hydroxy-3,4-seco-dammaran-4,24-dien-3-oic acid (dammarenolic acid) (2), (3β,20S)-3,20-dihydroxydammaran-24-ene (3), and (20S)-3-oxo-20-hydroxydammaran-24-ene (4). The tyrosine kinase assay of the four compounds resulted only 1 and 2 at concentration of 10 μM that had weak activity against EGFR and InsR, with their % inhibitory were 30%, 27% (1), 45%, and 32% (2), respectively. The results suggested that the presence of a linear carboxylic acid group in both compounds could be of significance to the inhibitory properties against the two RTKs.

• Archives of Pharmacal Research
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• 제26권12호
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• pp.1074-1078
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• 2003

The effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice was examined. A single administration of morphine (10 mg/kg, s.c.) induced hyperactivity as measured in mice. The morphine-induced hyperactivity was inhibited by pretreatment with glycine (100, 200 and 400 mg/kg, i.p.). In addition, it was found repeated administration of morphine (10 mg/kg, s.c.) to mice daily for 6 days caused an increase in motor activity which could be induced by a subsequent morphine dose, an effect known as reverse tolerance or sensitization. Glycine (100, 200 and 400 rng/kg, i.p.) also inhibited morphine-induced reverse tolerance. Mice that had received 7 daily repeated administrations of morphine also developed postsynaptic dopamine receptor supersensitivity, as shown by enhanced ambulatory activity after administration of apomorphine (2 mg/kg, s.c.). Glycine inhibited the development of postsynaptic dopamine receptor supersensitivity induced by repeated administration of morphine. It is suggested that the inhibitory effects of glycine might be mediated by dopaminergic (DAergic) transmission. Accordingly, the inhibition by glycine of the morphine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity suggests that glycine might be useful for the treatment of morphine addiction.

• 생약학회지
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• 제41권1호
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• pp.43-47
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• 2010

In order to screen new receptor tyrosine kinase inhibitor which is expected to be anticancer drug lead, we have investigated receptor tyrosine kinase inhibitory activity on the marine alga-derived symbiotic microorganisms (500 strains). The significant activities (over 70% inhibition at $10\;{\mu}g/ml$) were observed in the extracts of ten strains (Strain No.: MFA018, 019, 206, 242, 325, 335, 343, 344, 354, 356), isolated from marine red algae, five strains (Strain No.: MFA030, 126, 213, 324, 339), isolated from the brown algae, and one strain (Strain No.: MFA272), isolated from the marine green algae, respectively. Among the active strains, MFA019 and 356 showed strong receptor tyrosine kinase inhibitory activity with $IC_{50}$ values of 0.6 and $0.9\;{\mu}g/ml$, respectively.

• The Korean Journal of Physiology and Pharmacology
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• 제1권5호
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• pp.485-493
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• 1997

We investigated the effect of ${\alpha}-adrenergic$ and cholinergic receptor agonists on $Ca^{2+}$ current in adult rat trigeminal ganglion neurons using whole-cell patch clamp methods. The application of acetylcholine, carbachol, and oxotremorine ($50\;{\mu}M\;each$) produced a rapid and reversible reduction of the $Ca^{2+}$ current by $17{\pm}6%,\;19{\pm}3%,\;and\;18{\pm}4%$, respectively. Atropine, a muscarinic antagonist, blocked carbachol- induced $Ca^{2+}$ current inhibition to $3{\pm}1%$. Norepinephrine ($50\;{\mu}M$) reduced $Ca^{2+}$ current by $18{\pm}2%$, while clonidine ($50\;{\mu}M$), an ${\alpha}2-adrenergic$ receptor agonist, inhibited $Ca^{2+}$ current by only $4{\pm}1%$. Yohimbine, an ${\alpha}2-adrenergic$ receptor antagonist, did not block the inhibitory effect of norepinephrine on $Ca^{2+}$ current, whereas prazosin, an ${\alpha}1-adrenergic$ receptor antagonist, attenuated the inhibitory effect of norepinephrine on $Ca^{2+}$ current to $6{\pm}1%$. This pharmacology contrasts with ${\alpha}2-adrenergic$ receptor modulation of $Ca^{2+}$ channels in rat sympathetic neurons, which is sensitive to clonidine and blocked by yohimbine. Our data suggest that the modulation of voltage dependent $Ca^{2+}$ channel by norepinephrine is mediated via an α1-adrenergic receptor. Pretreatment with pertussis toxin (250 ng/ml) for 16 h greatly reduced norepinephrine- and carbachol-induced $Ca^{2+}$ current inhibition from $17{\pm}3%\;and\;18{\pm}3%\;to\;2{\pm}1%\;and\;2{\pm}1%$, respectively. These results demonstrate that norepinephrine, through an ${\alpha}1-adrenergic$ receptor, and carbachol, through a muscarinic receptor, inhibit $Ca^{2+}$ currents in adult rat trigeminal ganglion neurons via pertussis toxin sensitive GTP-binding proteins.

• 대한약리학회지
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• 제29권2호
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• pp.245-252
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• 1993

Amiloride는 $Na{^+}$ channels를 선택적으로 억제하는 potassium sparing diuretic이다. 본 연구에서는 amiloride와 아데노신 수용체의 상호작용을 밝히고자, 흰쥐에서 얻은 crude adipocytic membrane fractions의 adenylyl cyclase activity를 여러 조건하에서 측정하였다. 우선 GTP가 isoproterenol-stimulated adenylyl cyclase activity에 미치는 영향을 조사함으로서 $G_i$ protein (inhibitory guanine nucleotide binding protein)의 기능을 알아보았다. 그 결과 amiloride는 높은 GTP 농도에서 isoproterenol-stimulated adenylyl cyclase의 활성을 억제하는 것을 관찰할 수 없었다. 이와는 대조적으로 amiloride 존재 하에서 2-chloroadenosine을 사용하여 아데노신 수용체를 경유한 isoproterenol-stimulated adenylyl cyclase activity가 억제되는 정도를 측정하였을 때, 2-chloroadenosine의 농도에 따라 큰 변화 없거나 오히려 억제 효과가 더욱 크게 나타났다. 그러나 위와 같은 조건하에서 propranolol에 의한 isoproterenol-stimulated adenylyl cyclase activity의 억제는 amiloride에 의해서 유의하게 변하지 않는 것으로 보아서, 수용체를 매개로 한 $G_s$ protein의 기능은 amiloride에 의해 영향을 받지 않는 것으로 생각된다. 그리고 amiloride에 의해 증가된, 2-chloroadenosine-mediated adenylyl cyclase의 억제 효과는 150mM NaCl 존재 하에서도 그대로 유지되었다. 이러한 결과로 보아 amiloride는 아데노신 수용체와 결합하여 $G_i$ proteins과의 coupling을 용이하게 할 뿐만 아니라, $G_i$ protein을 선택적으로 변화시켜 $G_i$ protein의 GTP 의존적인 adenylyl cyclase의 억제 기능을 제거하는 두 작용을 갖는 것으로 사료된다.

• 대한의생명과학회지
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• 제11권2호
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• pp.175-183
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• 2005

The two major isoflavones in soy, genistein and daidzein, are well known to prevent hormone-dependent cancers by their anti estrogenic activity. The exact molecular mechanisms for the protective action are, however, not provided yet. It has been reported that genistein and daidzein have a potential anticancer activity through their antiproliferative effect in many hormone-dependent cancer cell lines. Transforming growth $factor-\beta1(TGF-\beta1)$ has also been found to have cell growth inhibitory effect, especially in mammary epithelial cells. This knowledge led to a hypothetical mechanism that the soy isoflavones-induced growth inhibitory effect can be derived from the regulation of $TGF-\beta1$ and $TGF-\beta$ receptors. In order to test this hypothesis, the effects of the soy isoflavones at various concentrations and periods on the expression of $TGF-\beta1$and $TGF-\beta$ receptors were investigated by using Northern blot analysis in human breast carcinoma epithelial cell lines, an estrogen receptor positive cell line (MCF-7) and an estrogen receptor negative cell line (MDA-MB-231). As a result, only genistein has shown a profound dose-dependent effect on $TGF-\beta1$ expression in the $ER^+$ cell line within the range of doses tested, and the expression levels are correspondent to their inhibitory activities of cell growth. Moreover, daidzein showed down-regulated $TGF-\beta1$ expression at a low dose, the cell growth proliferation was promoted at the same condition. Therefore, antiproliferative activity of the soy isoflavones can be mediated by $TGF-\beta1$ expression, and the effects are mainly, if not all, occurred by ER dependent pathway. The expression of $TGF-\beta$ receptors was induced at a lower dose than the one for $TGF-{\beta}1$ induction regardless of the presence of ER, and the expression patterns are similar to those of the cell growth inhibition. These results indicated that the regulation of $TGF-\beta$ receptor expression as well, prior to $TGF-\beta1$ expression, may be involved in the antiproliferative activity of soy isoflavones. Little or no expression of $TGF-\beta$ receptors was found in the MCF-7 and MDA-MB-231 cells, suggesting refractory properties of the cells to growth inhibitory effect of the $TGF-\beta$. The soy isoflavones can seemingly restore the sensitivity of growth inhibitory responses to $TGF-\beta1$ by re-inducing $TGF-\beta$ receptors expression. In conclusions, our findings presented in this study show that the antitumorigenic activity of the soy isoflavones could be mediated by not only $TGF-\beta1$induction but $TGF-\beta$ receptor restoration. Thus, soy isoflavones could be good model molecules to develop new nonsteroidal antiestrogenic chemopreventive agents, associated with, regulation of $TGF-\beta$ and its receptors.

• Nuclear Medicine and Molecular Imaging
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• 제41권2호
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• pp.166-171
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• 2007

GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, $GABA_{A}-receptor$ that allows chloride to pass through a ligand gated ion channel and $GABA_{B}-receptor$ that uses G-proteins for signaling. The $GABA_{A}$-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate $GABA_{A}$-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with $^{11}C-FMZ$, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, $^{18}F-fluoroflumazenil$ (FFMZ) has been developed to overcome $^{11}C's$ short half-life. $^{18}F-FFMZ$ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using $^{11}C-FMZ$ PET instead of $^{18}F-FDG$ PET, restrict the foci better and may also help find lesions better than high resolution MR. $GABA_{A}$ receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, $GAB_{A}$ imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

• Natural Product Sciences
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• 제27권2호
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• pp.134-139
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• 2021

A new cipadesin limonoid, i.e. 3-epi-cipadonoid C (1), and a new tirucallane triterpene, i.e. hispidol B 3-palmitate (3), have been isolated from the seeds and fruit peels extract of Sandoricum koetjape, respectively. Along with these compounds the known limonoid, cipaferen G (2), and two pentacyclic triterpenes, bryonolic (4) and bryononic (5) acids, were also isolated. The strucrures of the new compounds were elucidated by the analysis of NMR and mass spectral data. Compounds 1 - 5 were evaluated as the inhibitor of receptor tyrosine kinases (EGFR, Epidermal Growth Factor Receptor; HER2, HER4, Human Epidermal growth factor Receptor 2, -4; IGFR, Insulin-like Growth Factor Receptor; InsR, Insulin Receptor; KDR, Kinase insert Domain Receptor; PDGFRα, and PDGFRβ, Platelet-Derived Growth Factor Receptor-α and -β). The results showed only 1 and 3 that have weak activity against InsR.

• 대한약리학회지
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• 제19권1호
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• pp.85-92
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• 1983

Intestine is innervated by an interconnected plexus of both sympathetic and parasympathetic nerve fibers. Sympathetic influence causes inhibition of intestinal motility mediated by both ${\alpha}-\;and\;{\beta}-adrenergic$ receptors. The mechanism of intestinal relaxation by ${\beta}-receptors$ has been extensively studied, but the function of ${\alpha}-receptors$ in intestinal motility is still unclear. Although it is suggested that catecholamine reduces acetylcholine release and this may play an important role in ${\alpha}-receptor$ mediated intestinal relaxation, there is no definite evidences about the mechanism and site of action of ${\alpha}-receptor$ mediated relaxation. In this experiment, therefore, the effect and site of action of ${\alpha}-receptor$ agonists were investigated in the guinea pig ileum using electrical field stimulation. The results are summarized as follows : 1) Electrical field stimulation elicited tonic contraction in isolated guinea pig ileum ana this contraction was completely inhibited by the pretreatment of tetrodotoxin or atropine. 2) Norepinephrine, epinephrine and dopamine inhibited the contraction induced by electrical field stimulation but methoxamine and phenylephrine had little effects. 3) Inhibitory effects of norepinephrine and dopamine was partially blocked by yohimbine and phentolamine pretreatment. But haloperidol and propranolol pretreatment cause no effects on the electrical field stimulation induced contraction. Inhibitory effect of dopamine was completely blocked by both haloperidol and yohimbine pretreatment. 4) Inhibitory effects of norepinephrine and dopamine were little affected by the pretreatment with hexamethonium. It is suggested that electrical field stimulation causes tonic contraction of guinea pig ileum by releasing acetylcholine from postganglionic fiber, and this release is blocked by presynaptic ${\alpha}-receptor$ activation.

• 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.