• 생명과학회지
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• 제21권4호
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• pp.481-485
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• 2011

T0901317은 핵수용체 전사인자인 liver X receptor (LXR, NR1H2/3)의 강력한 합성 리간드이다. 그러나, T0901317은 farnesoid X receptor (FXR, NR1H4)와 pregnane X receptor (PXR, NR1I2)에 대해 작용물질(agonist) 로, androgen receptor (AR, NR3C4)와 rertinoid-related orphan receptor-${\alpha}$ (ROR-${\alpha}$, NR1F1)에 대해 길항제(antagonist)로 작용하여, LXR외에 적어도 다른 4종의 핵수용체에 대해 그 활성을 조절한다고 보고되었다. 우리는 T0901317이 또 다른 핵수용체인 constitutive androstane receptor (CAR, NR1I3)에 대해 저해제로 기능함을 확인 하였다. CAR는 이미 T0901317에 의해 기능이 조절된다고 알려진 PXR, FXR, LXR과 더불어 간에서 생체이물과 콜레스테롤의 대사작용에 중요한 역할을 하므로 T0901317에 의해 CAR의 활성이 조절된다는 사실은, 간세포에서 T0901317을 이용한 실험 결과를 해석할 때 세포 내에 이미 존재하는 이들 핵수용체 단백질의 영향을 고려하여 주의깊게 해석해야 함을 의미한다.

• Biomolecules & Therapeutics
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• 제13권3호
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• pp.138-142
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• 2005

Adenosine and GABA are known to be major inhitory neurotransmitters in the central nervous system and its receptors mediate various neurophamacological effects including cardiovascular modulatory effects. Inhibitory cardiovascular effects induced by intrathecal (i.t.) administration of adenosine $A_1$ receptor agonist and its modulation by cyclic AMP was suggested by our previous report. In this experiment, we examined the modulation of cardiovascular effects of adenosine $A_1$ receptor and adenosine $A_2$ receptor by $GABA_B$ receptors antagonist in the spinal cord. I.t. administration of 10 nmol of $N^6$-cyclohexyladenosine (CHA, an adenosine $A_1$ receptor agonist), I.t. administration of 2 nmol of 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA, an adenosine $A_2$ receptor agonist), pretreatment with 5-aminovaleric acid (a $GABA_B$ receptor antagonist, 50 nmol, i.t.) prior to administration of CHA and pretreatment with 5-aminovaleric acid (a $GABA_B$ receptor antagonist, 50 nmol, i.t.) prior to administration of CPCA were performed in anesthetized, artificially ventilated Sprague-Dawley rats. I.t. administration of 50 nmol of 5-aminovaleric acid significantly attenuated the inhibitory cardiovascular effects of CHA but did not attenuated the inhibitory cardiovascular effects of CPCA. It is suggested that cardiovascular responses of adenosine $A_1$ receptor is modulated by $GABA_B$ receptor and adenosine $A_2$ receptor is not modulated by $GABA_B$ receptor in the spinal cord.

• 약학회지
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• 제36권5호
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• pp.496-505
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• 1992

The correlation between GABA receptors($GABA_A$ and $GABA_B$ receptor) and benzodiazepine receptor on the saline infusion-induced micturition reflex contraction was studied in the female rat. To investigate the effect of ${\gamma}-aminobutyric$ acid(GABA) on the micturition reflex, exogenous GABA(10 mg/kg) and GABA transaminase inhibitor(aminooxyacetic acid; AOAA $1\;{\mu}g$) were administered intravenously(i.v.) and intracerebroventriculary(i.c.v.), respectively. In result, both GABA and AOAA inhibited the saline induced micturition reflex contraction. This AOAA induced inhibition of micturition reflex was blocked by both bicuculine. $GABA_A$ receptor antagonist, and Ro 15-1788, benzodiazepine receptor antagonist. Muscimol, $GABA_A$ receptor antagonist($0.1\;{\mu}g$ i.c.v., $3\;{\mu}g$ intrathecal; i.t., 1 mg/kg i.v.) and baclofen, $GABA_A$ receptor agonist($1\;{\mu}g$ i.c.v., $3\;{\mu}g$ i.t., 1 mg/kg i.v.) also inhibited the bladder contraction. Pretreatment of bicuculline($1\;{\mu}g$ i.c.v.), but not of 5-aminovaleric acid(AVA, $1\;{\mu}g$ i.c.v.), $GABA_B$ receptor antagonist blocked the central inhibition of muscimol. These inhibitory effects were reversed by Ro15-1788 but were potentiated by flurazepam, benzodiazepine receptor antagonist. On the other hand, the inhibitory effects of baclofen were not affected by Ro 15-1788. Diazepam and flurazepam also inhibited the micturition reflex contraction when they were administered $3\;{\mu}g$ i.c.v., $10\;{\mu}g$ i.t., $10\;{\mu}M$, $30\;{\mu}M$ transurethrally, respectively. In conclusion, these results suggest that the micturition reflex is mediated by $GABA_A$, $GABA_B$ receptor and benzodiazepine receptor. The bezodiazepines increase the receptor binding of GABA to the $GABA_A$ receptor, so that the benzodiiazepines show the synergistic effect on the inhibition of the micturition reflex contraction, but not to the $GABA_B$ receptor.

• 통합자연과학논문집
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• 제11권1호
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• pp.9-13
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• 2018

KiSS1-derived peptide receptor, a GPCR protein, binds with the hormone Kisspeptin plays a major role in the neuroendocrine regulation of reproduction. It is important in the onset of puberty and triggers the release of gonadotrophin-releasing hormone. It is a potential drug target for the disorders related to GnRH, hence, analysing the structural features of the receptor becomes important. The three dimensional of the receptor modelled in a previous study was utilised. In this study, we have analysed the protein - protein interaction of the receptor with Kisspeptin 10 and 15. The study revealed the important residues which are involved in the interaction. The result of this study could be helpful in understanding the mechanism of Kiss1 receptor activation and the pathophysiology of the disorders related to the receptor.

• 비만대사연구학술지
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• 제1권1호
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• pp.4-13
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• 2022

Currently, pharmacotherapy is becoming essential for obesity, owing to its expanding and increasing epidemiology. In this review, novel peptide-based drugs of four classes are covered: GLP-1 receptor agonist, GIP/GLP-1 receptor dual agonist, glucagon/GLP-1 receptor dual agonist, and a combination of amylin receptor agonist/GLP-1 receptor agonist. Semaglutide is a next-generation GLP-1 receptor agonist with a longer duration and stronger weight and glucose reduction effects than liraglutide and dulaglutide. In the STEP1 trial, semaglutide 2.4 mg reduced body weight by approximately 15% in people with obesity with similar or milder adverse events than liraglutide 3.0 mg. Tirzepatide, a GIP/GLP-1 receptor dual agonist, also has a long duration and strong weight- and glucose-lowering effect. According to SURPASS-2, 3, and 4, in patients with BMI≥25 kg/m² and type 2 diabetes mellitus (T2DM), tirzepatide 15 mg reduced the initial body weight by >13%. Cotadutide, a glucagon/GLP-1 receptor dual agonist, showed weaker weight-lowering effects than semaglutide and tirzepatide, while it was comparable to that of liraglutide in a phase 2 clinical trial for non-alcoholic fatty liver disease in patients with BMI≥25 kg/m² and T2DM. Additionally, its effect on the liver was noticeable. The long-acting amylin receptor agonist cargrilintide combined with semaglutide can be another effective option for obesity treatment. Even in a small phase 1 trial with a short study period of 20 weeks, cargrilintide 2.4 mg/semaglutide 2.4 mg reduced by 17% of initial body weight in people with BMI 27-39.9 kg/m². In coming several years, semaglutide, tirzepatide, and cargrilintide/semaglutide will become available for obesity treatment in Korea.

• 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.

• 생물정신의학
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• 제12권2호
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• pp.107-113
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• 2005

Purpose:In an attempt to predict the interpersonal differences of therapeutic response to antipsychotic drugs on pharmaco-genetic bases, this study was designed to investigate the relationship between the therapeutic response to antipsychotic drugs and Taq I A dopamine $D_2$ receptor polymorphism in schizophrenic patients. Methods:The subjects were 158 patients diagnosed with schizophrenia(DSM-IV). The therapeutic response to antipsychotic drugs was evaluated using the Treatment Response Scale(TRS) retrospectively. Patients were divided into two groups, dopamine receptor antagonist responders, and serotonin-dopamine antagonist responders. The patients' Taq I A dopamine $D_2$ receptor polymorphism was determined by polymerase chain reaction(PCR) and restriction fragment length polymorphism(RFLP). Results:The dopamine receptor antagonist responders had the A1 allele in significantly higher incidences (${\chi}^2$(1)=4.875, p=0.027, two-tailed). No significant difference was found among the serotonin-dopamine antagonist responders between those with or without the A1 allele. Conclusions:The patients with the A1 allele responded better to dopamine receptor antagonists than those with no A1 allele. Based on these results, it is suggested that the pharmacological effect of dopamine receptor antagonists can be predicted depending on the presence of the A1 allele in schizophrenic patients.

• 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.

• The Korean Journal of Physiology and Pharmacology
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• 제2권1호
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• pp.31-39
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• 1998

As it has been reported that the depolarization induced acetylcholine (ACh) release is modulated by activation of presynaptic $A_1$ adenosine heteroreceptor and various lines of evidence suggest the $A_2$ adenosine receptor is present in the hippocampus. The present study was undertaken to delineate the role of adenosine receptors on the hippocampal ACh release. Slices from the rat hippocampus 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, $5\;V/cm^{-1}$, 2 min), was measured, and the influence of various adenosine receptor-related agents on the evoked tritium outflow was investigated. And also, the drug-receptor binding assay was performed in order to confirm the presence of $A_1$ and $A_2$ adenosine receptors in the rat hippocampus. N-ethylcarboxamidoadenosine (NECA), a potent adenosine receptor agonist with nearly equal affinity at $A_1$ and $A_2$ adenosine receptors, in concentrations ranging from $1{\sim}30\;{\mu}M$, decreased the electrically-evoked $[^3H]ACh$ release in a concentration-dependent manner without affecting the basal rate of release. And the effect of NECA was significantly inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 ${\mu}M$), a selective $A_1$ adenosine receptor antagonist, but was not influenced by 3,7-dimethyl-1-propargylxanthine (DMPX, 5 ${\mu}M$), a specific $A_2$ adenosine receptor antagonist. $N^6-cyclopentyladenosine$ (CPA), a selective $A_1$ adenosine receptor agonist, in doses ranging from 0.1 to 10 ${\mu}M$, reduced evoked $[^3H]ACh$ release in a dose-dependent manner without the change of the basal release. And the effect of CPA was significantly inhibited by 2 ${\mu}M$ DPCPX treatment. 2-P-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680C), a potent $A_2$ adenosine receptor agonist, in concentrations ranging from 0.1 to 10 ${\mu}M$, did not alter the evoked ACh release. In the drug-receptor binding assay, the binding of $[^3H]2-chloro-N^6-cyclopentyladenosine$ ($[^3H]$CCPA) to the $A_1$ adenosine receptor of rat hippocampal membranes was inhibited by CPA ($K_i$ = 1.22 nM), NECA ($K_i=10.17 nM$) and DPCPX ($K_i=161.86 nM$), but not by CGS-21680C ($K_i=2,380 nM$) and DMPX ($K_i=22,367 nM$). However, the specific binding of $[^3H]CGS-21680C$ to the $A_2$ adenosine receptor was not observed. These results suggest that the $A_1$ adenosine heteroreceptor play an important role in evoked ACh release, but the presence of $A_2$ adenosine receptor is not confirmed in this study.

• 대한약리학회지
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• 제30권1호
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• pp.49-57
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• 1994

Oxomemazine이 muscarinic receptor subtypes에 대하여 선택성을 가지는지에 관한 지견을 얻고자, 대뇌, 심실 및 회장 muscarinic receptor에 대한 oxomemazine의 결합성질을 조사, 비교하였다. $[^3H]QNB$ 포화결합실험 결과 세 조직의 muscarinic receptor는 $[^3H]QNB$에 대해서는 affinity가 약 60pM인 단일 receptor인 것으로 추정되었다. 대뇌에서 pirenzepine과 oxomemazine의 $[^3H]QNB$ 결합억제에 대한 Hill coefficient는 각각 0.67 및 0.8로서 대뇌에는 이들 약물에 대하여 affinity가 서로 다른 두 종류의 muscarinic receptor subtypes가 존재하는 것으로 나타났으며, pirenzepine에 대한 high $affinity(M_1)$와 $low affinity(M_2)$ receptor 및 oxomemazine에 대한 high $affinity(O_H)$와 $low\;affinity (O_L)$ receptor의 분포비는 약 60:40 및 40:60이었고, $M_1$과 $M_2$ receptor에 대한 pirenzepine의 $K_i$치는 16nM 및 431 nM, $O_H$와 $O_L$, receptor에 대한 oxomemazine 의 $K_i$치는 80nM 및 1350nM이었다. 그러나 심실과 회장에서 이들 약물의 $[^3H]QNB$ 결합억제에 대한 Hill coefficient는 1에 가까웠다. 심실과 회장 muscarinic receptor에 대한 pirenzepine의 $K_i$치는 850nM 및 250nM, oxomemazine의 $K_i$치는 1460nM 및 670nM로서 대피에서 이들 약물의 low affinity receptor에 대한 $K_i$치에 가까웠다. 즉, muscarinic receptor에 대한 affinity면에서 oxomemazine은 pirenzepine과 같이 대뇌에서 가장 높았으며, 회장에 대해서는 중등도였고, 심실에서 가장 낮았다. 이로 보아 oxomemazine은 $M_1\;receptor$에 선택성이 있는 것으로 추정된다.