• Journal of Pharmaceutical Investigation
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• 제39권5호
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• pp.327-331
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• 2009

5-HT$_{2C}$ receptors have been considered as therapeutic targets for the treatment of various central nervous system disorders such as depression, anxiety, epilepsy, schizophrenia and sleep disorders. We chemically synthesized KKHQ80109 (K09) and KKHQ80114 (K14), selective 5-HT$_{2C}$ agonists, with the purpose of developing therapeutic agents for the treatment of obesity. The objective of this work is to investigate pharmacokinetic parameters and bioavailability of K09 and K14 in rats given orally or intravenously. Oral administration of 20 mg/kg K09 results in 4.11 hr of the terminal half-life and 89.16 ng/mL of C$_{max}$ at 5.00 hr (T$_{max}$). The terminal half-life of K14 was 3.83 hr with 215.81 ng/mL of C$_{max}$ at 3.33 hr (T$_{max}$) after oral dosing of 20 mg/kg K14, indicating that K14 is more rapidly absorbed than K09. Bioavailability showed 0.17-0.21 for K09 and 0.19-0.23 for K14. Urinary excretion of parent K09 and K14 was less than 1%, indicating that K09 and K14 undergo very extensive hepatic metabolism.

• Genomics & Informatics
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• 제5권2호
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• pp.77-82
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• 2007

Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol-1,4,5-triphosphate/calcium $(InsP3/Ca^{2+})$ signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and neuromodulin secretion in rat hypothalamic neurons. Specific mRNA transcripts for 5-HT1A, 5-HT2C and 5-HT4 were identified in rat hypothalamic neurons. These experiments were supported by combined techniques such as cAMP and a $Ca^{2+}$ assays in order to elucidate the associated receptors and signaling pathways. The cAMP production and neuromodulin release were profoundly inhibited during the activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor stimulated InsP3 production and caused $Ca^{2+}$ release from the sarcoplasmic reticulum. Selective activation of the Gs-coupled 5-HT4 receptor also stimulated cAMP production, and caused an increase in neuromodulin secretion. These findings demonstrate the ability of 5-HT receptor subtypes expressed in neurons to induce neuromodulin production. This leads to the activation of single or multiple G-proteins which regulate the $InsP3/Ca^{2+}/PLC-{\gamma}$ and adenyl cyclase / cAMP signaling pathways.

• The Korean Journal of Physiology and Pharmacology
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• 제4권5호
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• pp.361-367
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• 2000

Cocaine functions as indirect dopamine and serotonin (5-hydroxytryptamine, 5HT) agonists and induces genomic and behavioral alterations in the striatum. Previously we demonstrated that ritanserin, a 5HT2/1C receptor antagonist, is not responsible for cocaine-induced behavioral alterations and zif268 mRNA gene expression in the striatum (see the previous paper in this issue). In this study, it was hypothesized that dopamine and 5HT2/1C receptors are required for cocaine-induced behavioral alterations and c-fos and zif268 mRNA expression. This hypothesis was addressed by infusing amperozide which antagonizes both 5HT2/1C and dopamine receptors and was analyzed using the quantitative in situ hybridization histochemistry in vivo. Systemic injection of amperozide (5 mg/kg, s.c.) significantly blocked increase in behavior, c-fos and zif268 mRNA expression induced by 15 mg/kg cocaine, i.p., in the dorsal striatum. These data suggest that dopamine and 5HT2/1C receptors are necessary for cocaine-induced behavioral alterations and immediate early gene expression in the dorsal striatum.

• Bulletin of the Korean Chemical Society
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• 제32권6호
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• pp.2008-2014
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• 2011

Serotonin or 5-hydroxytryptamine subtype 2C ($5-HT_{2C}$) receptor belongs to class A amine subfamily of G-protein-coupled receptor (GPCR) super family and its ligands has therapeutic promise as anti-depressant and -obesity agents. So far, bovine rhodopsin from class A opsin subfamily was the mostly used X-ray crystal template to model this receptor. Here, we explained homology model using beta 2 adrenergic receptor (${\beta}$2AR), the model was energetically minimized and validated by flexible ligand docking with known agonists and antagonists. In the active site Asp134, Ser138 of transmembrane 3 (TM3), Arg195 of extracellular loop 2 (ECL2) and Tyr358 of TM7 were found as important residues to interact with agonists. In addition to these, V208 of ECL2 and N351 of TM7 was found to interact with antagonists. Several conserved residues including Trp324, Phe327 and Phe328 were also found to contribute hydrophobic interaction. The predicted ligand binding mode is in good agreement with published mutagenesis and homology model data. This new template derived homology model can be useful for further virtual screening based lead identification.

• The Korean Journal of Physiology and Pharmacology
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• 제20권6호
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• pp.605-611
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• 2016

Ketamine is an anesthetic with hypertensive effects, which make it useful for patients at risk of shock. However, previous ex vivo studies reported vasodilatory actions of ketamine in isolated arteries. In this study, we reexamined the effects of ketamine on arterial tones in the presence and absence of physiological concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) by measuring the isometric tension of endothelium-denuded rat mesenteric arterial rings. Ketamine little affected the resting tone of control mesenteric arterial rings, but, in the presence of 5-HT (100~200 nM), ketamine ($10{\sim}100{\mu}M$) markedly contracted the arterial rings. Ketamine did not contract arterial rings in the presence of NE (10 nM), indicating that the vasoconstrictive action of ketamine is 5-HT-dependent. The concentration-response curves (CRCs) of 5-HT were clearly shifted to the left in the presence of ketamine ($30{\mu}M$), whereas the CRCs of NE were little affected by ketamine. The left shift of the 5-HT CRCs caused by ketamine was reversed with ketanserin, a competitive 5-$HT_{2A}$ receptor inhibitor, indicating that ketamine facilitated the activation of 5-$HT_{2A}$ receptors. Anpirtoline and BW723C86, selective agonists of 5-$HT_{1B}$ and 5-$HT_{2B}$ receptors, respectively, did not contract arterial rings in the absence or presence of ketamine. These results indicate that ketamine specifically enhances 5-$HT_{2A}$ receptor-mediated vasoconstriction and that it is vasoconstrictive in a clinical setting. The facilitative action of ketamine on 5-$HT_{2A}$ receptors should be considered in ketamine-induced hypertension as well as in the pathogenesis of diseases such as schizophrenia, wherein experimental animal models are frequently generated using ketamine.

• Journal of Pharmaceutical Investigation
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• 제39권5호
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• pp.321-325
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• 2009

5-HT$_{2C}$ receptors have been considered as therapeutic targets for the treatment of various central nervous system disorders such as depression, anxiety, epilepsy, schizophrenia and sleep disorders. We chemically synthesized KKHQ80114 (K14) and KKHQ80109 (K09), selective 5-HT$_{2C}$ agonists, with the purpose of developing therapeutic agents for the treatment of obesity. The objective of this work is to investigate analytical methods of these compounds in the plasma and urine of rats by gas chromatography/mass spectrometry. In this experiment, K14 was determined in plasma and urine by using K09 as internal standard. Calibration curves give a good linearity in plasma (r$^2$=0.9993) and urine (r$^2$=0.9988). Among hexane, ethyl acetate and diethyl ether, the highest peak was observed in diethyl ether. However, ethyl acetate was used since more interfering peaks were observed with diethyl ether. Inter-day precision and accuracy were determined in the ranges of 50-500 ng/mL for plasma and 10-500 ng/ml for urine. Quantitation limits were 50 ng/mL plasma and 25 ng/ mL urine. These data may be applicable for further studies of these compounds including absorption and metabolism due to no pharmacokinetic or analytical data available.

• 대한약리학회지
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• 제20권2호
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• pp.15-21
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• 1984

Clonidine으로 고혈압을 치료시 부작용으로 진정작용이 심하게 나타나며 이는 Clonidine이 중추 ${\alpha}_2$-수용체를 흥분시켜서 일으킨 결과임이 보고되었다. 본 실험에서는 부화 $1{\sim}2$일이 된 병아리에 ${\alpha}_2$-수용체 효현제들을 주사하여 정좌반사가 소실될 때까지의 시간 및 수련시간을 관찰하였으며, 그리고 guanabenz 유도 수면에 대한 ${\alpha}_1$- 및 ${\alpha}_2$-수용체 길항제 및 opiate수용체 길항제가 어떻게 관여하는 지를 검토하고 다음과 같이 요약하였다. 1) ${\alpha}_2$-수용체 효현제중 guanabenz, clonidine, guanfacine 및 B-HT 933은 용량에 의존해서 정좌반사소실까지의 잠복시간을 감소시켰다. 그러나 B-HT 920 및 oxymetazoline은 잠복시간을 경미하게 연장시켰다. 2) ${\alpha}_2$-수용체 효현제들은 용량에 비례해서 수면시간을 증가시켰고 이들의 강도는 guanabenz>clonidine>oxymetazoline${\geq}$B-HT 933${\geq}$B-HT 920> guanfacine의 순위이었다. 3) ${\alpha}_2$-수용체 길항제들은 양에 비례해서 guanabenz 유도 수면시간을 감소시켰으며 이들의 강도는 yohimbine>rauwolscine>piperoxan${\geq}$RX 781094의 순위 이었다. 4) Ethanol 및 hexobarbital유도 수면은 yohimbine에 의해 봉쇄되지 아니하였다. 5) Guanabenz유도 수면시간에 대해서 ${\alpha}_1$-수용체 효현제인 methoxamine 및 Phenylephrine은 영향이 없었으나, ${\alpha}_1$-수용체 결항제인 Prazosin은 증가시켰다. 그러나 corynanthine은 반대로 수면시간을 현저히 감소시켰다. 이상의 결과로 보아 중추 ${\alpha}_2$-수용체의 흥분으로 병아리의 수면이 야기되고, 중추 ${\alpha}_1$-수용체의 역할에 대하여는 명백하지 않으나 ${\alpha}_2$-수용체 효현제 및 길항제의 성질을 규명하는 동물모델로서 부화 I${\sim}$2일의 병아리가 크게 유용할 것으로 시사되는 바이다.