• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1992년도 제1회 신약개발 연구발표회 초록집
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• pp.39-39
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• 1992

5-Hydroxytryptamine(serotonin, 5-HT)은 중추신경의 신경 전달물질로서 조울병, 불안신경증 등의 정신병태생리에 중요한 역할을 한다. Radioligand 결합실험에 의하여 5-$HT_{1A}$, 5-$HT_{1B}$, 5-$HT_{1C}$, 5-$HT_{1D}$, 5-$HT_{2}$, 5-$HT_3$의 5-HT receptor subtypes의 존재가 확인되어 있고, 그 중에서도 5-$HT_{1A}$ receptor는 중추작용 증 정 도의 조절에 관계가 깊은 raphe nuclei 및 해마에 주로 존재하여 약리학적으로는 체온강하, 혈압 강하, 과식작용, corticosterone 분비 등과 관련되어 있음이 알려져 있다. 따라서 본 수용체 agonist가 항불안약, 항우울약 또는 항고혈압약으로서의 응용이 가능해지면서 5-$HT_{1A}$ 수용체 기능의 해명 및 그 agonist의 개발이 주목받고 있는 가운데, 본 연구에 있어서, 항불안약 개발목적으로 합성된 일련의 화합물 중 1-<3-(3,4-methylene-dioxyphenoxy)propyl> 4-phenyl piperazine (DP-554)이 5-HT 수용체에 특이적이고 선택적으로 높은 친화성을 가지며, rat 해마의 막분획에서 adenylate cyclase 활성을 억제하고, 뇌내 5-HT turnover rate를 감소시키는 둥의 약리학적 작용을 나타내어, 이 화합물이 5-$HT_{1A}$ receptor agonist로서 작용함을 밝혔다. Mouse vas deferens (MVD)를 이용한 실험에서 5-$HT_{1A}$ receptor가 MVD의 교감신경 말단에 존재하여 그 neurotransmission을 억제함이 시사되었으며, 이 조직에서 또한 5-$HT_2$와 5-$HT_3$ 수용체의 존재를 확인하고 각각의 기능을 분명히 했다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.282-282
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• 1994

Radioligand결합실험에 의하여 7가지 이상의 5-hydroxytryptamine serotonin, 5-HT)수용체 subtype가 규명되어 있고, 1983년 5-HT agonist로 알려져 있던 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)가 〔$^3$H〕5-HT수용체에 대한 결합만을 선택적으로 억제하며, 본 수용체를 직접 표식함이 알려진 이래, 본 수용체의 기능에 대한 연구가 계속되어 오고있다. 특히 항불안약으로 임상에 사용되어 왔던 benzodiazepines이 5-HT neuron의 활성을 억제한다는 사실이 보고되면서 5-HT neuron과 불안과의 관련에 관한 연구가 계속되고 있는 가운데, 새로운 항불안약으로 주목을 받고 있던 buspirone이 5-$HT_{1A}$ 수용체에 높은 친화성을 가짐이 확인되었다. 그 외에도 5-$HT_{1A}$ 수용체작용약이 항우울약, 항고혈압약으로서의 응용가능성 이 시사되면서 본 수용체작용약의 개발 및 그 기능해명이 주목을 받고 있다. 본 연구에서는, 5-$HT_{1A}$ 수용체작용약인 8-OH-DPAT와 항불안약을 개발할 목적으로 합성된 화합물인 1-[3-(3,4-methylenedioxyphenoxy)propy〕-4-phenyl piperazine (8P-554)을 이용하여, 화합물의 5-HT$_{1A}$수용체에 대한 친화성을 검토하는 방법과. 본 수용체를 통하여 나타난다고 알려져 있는 5-HT의 약리작용을 검토하는 방법을 기술하므로서, 여러가지 임상적 응용을 위하여 새롭게 합성되는 화합물의 5-$HT_{1A}$ 수용체와의 상호작용을 검색하는 방법을 제시하고자 한다.다.

• The Korean Journal of Physiology and Pharmacology
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• 제21권2호
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• pp.169-177
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• 2017

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine $(5-HT)_3$ receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine ($1{\sim}300{\mu}M$) resulted in a concentration-dependent reduction in peak amplitude of currents induced by $3{\mu}m$ of 5-HT for an $IC_{50}$ value of $28.2{\pm}3.6{\mu}M$ with a Hill coefficient of $1.2{\pm}0.1$. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, $5-HT_3$-mediated currents evoked by 1 mM dopamine, a partial $5-HT_3$ receptor agonist, were inhibited by lamotrigine co-application. The $EC_{50}$ of 5-HT for $5-HT_3$ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate $5-HT_3$ receptor desensitization, inhibited $5-HT_3$ receptor currents in a concentration-dependent manner. The deactivation of $5-HT_3$ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of $5-HT_3$ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the $5-HT_3$ receptor currents. These results indicate that lamotrigine inhibits $5-HT_3$-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

• 한국동물생명공학회지
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• 제38권2호
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• pp.77-83
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• 2023

Background: Serotonin receptors can be divided into seven different families with various subtypes. The serotonin 1A (5-HT1A) receptor is one of the most abundant subtypes in animal brains. The expression of 5-HT1A receptors in the brain has been reported in various animals but has not been studied in horses. The 5-HT1A receptor functions related to emotions and behaviors, thus it is important to understand the functional effects and distribution of 5-HT1A receptors in horses to better understand horse behavior and its associated mechanism. Methods: Brain samples from seven different regions, which were the frontal, central, and posterior cerebral cortices, cerebellar cortex and medulla, thalamus, and hypothalamus, were collected from six horses. Western blot analysis was performed to validate the cross-reactivity of rabbit anti-5-HT1A receptor antibody in horse samples. Immunofluorescence was performed to evaluate the localization of 5-HT1A receptors in the brains. Results: The protein bands of 5-HT1A receptor appeared at approximately 50 kDa in the frontal, central, and posterior cerebral cortices, cerebellar cortex, thalamus, and hypothalamus. In contrast, no band was observed in the cerebellar medulla. Immunofluorescence analysis showed that the cytoplasm of neurons in the cerebral cortices, thalamus, and hypothalamus were immunostained for 5-HT1A receptors. In the cerebellar cortex, 5-HT1A was localized in the cytoplasm of Purkinje cells. Conclusions: In conclusion, the study suggests that 5-HT and 5-HT1A receptor systems may play important roles in the central nervous system of horses, based on the widespread distribution of the receptors in the horse brain.

• The Korean Journal of Physiology and Pharmacology
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• 제15권5호
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• pp.267-272
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• 2011

A number of studies have demonstrated that 5-hydroxytryptamine (5-HT) can induce muscle contraction or relaxation response and enhance secretion in the gastrointestinal tract via a multiplicity of 5-HT receptor subtypes. In the present study, we investigated the pharmacological characterization of the 5-HT-induced contractile response in longitudinal smooth muscle isolated from the feline ileum. Addition of 5-HT into muscle chambers enhanced the basal tone and spontaneous activity in a concentration-dependent manner. The neurotoxin tetrodotoxin did not alter the 5-HT-induced contraction of the longitudinal muscles. Neither atropine nor guanethidine affected the contraction. The 5-HT agonists, 5-methylserotonin hydrochloride and mosapride, also evoked concentration-dependent contractions. The 5-HT-induced contraction was enhanced by the $5HT_2$ receptor antagonist ketanserin and the $5-HT_3$ receptor antagonist ondansetron but was inhibited by the 5-$HT_1$ receptor antagonist methysergide and 5-$HT_4$ receptor antagonist GR113808. These results indicate that 5-$HT_1$ and 5-$HT_4$ receptors may mediate the contraction of the 5-HT-induced response and 5-$HT_2$ and 5-$HT_3$ receptors may mediate 5-HT-induced relaxation in feline ileal longitudinal smooth muscles.

• 대한약리학회지
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• 제28권2호
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• pp.137-146
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• 1992

신장기능조절에 있어서 중추 tryptamine계가 관련되어 있으며, $5-HT_1$수용체는 이뇨적인 역할을 하고 있는 반면에 $5-HT_2$ 및 $5-HT_3$수용체는 항이뇨적인 영향을 미치고 있음이 밝혀진 바 있다. 또한 $5-HT_1$수용체도 단일하지 않고 여러 subtype가 존재함이 알려져 있다. $5-HT_{1A}$수용체의 역할에 관해서는 신기능에 이뇨적인 영향을 미치고 있음이 시사된 바 있다. 본 연구에서는 중추 tryptamine성 신기능 조절에 있어서 $5-HT_{1B}$수용체의 역할을 구명하고자 하였다. 선택적 $5-HT_{1B}$ agonist인 TFMPP $8{\sim}750\;{\mu}g/kg$을 가토 측뇌실내로 투여하면 투여량에 비례하여 이뇨 및 Na과 K 배설의 증가를 초래하였으며, $250\;{\mu}g/kg$ 투여시에는 Na의 배설 분획이 5.44%까지 증가하였다. Na배설 촉진작용은 신혈류역학의 증가 보다도 훨씬 지속하여, 세뇨관에서의 Na재흡수 감소작용이 체액성 기전임을 시사하였다. TFMPP $250\;{\mu}g/kg$ icv투여시에 natriuresis와 함께 혈장내 atrial natriuretic peptide 농도가 약 6배 증가되었다. TFMPP $250\;{\mu}g/kg$을 정맥내로 투여하였을때는 뇌실내 투여시와는 상이하게 신기능에 별다른 유의한 변동을 초래하지 않았다. 이와같은 TFMPP의 diuresis 및 natriuresis는 각각 $5-HT_2$ 및 $5-HT_3$ 수용체의 선택적 antagonist인 ketanserin과 MDL 72222의 전처치에 의하여 차단되지 않았으며, methysergide에 의해서도 억제되지 않았다. 또한 $5-HT_{1A}$ antagonist로 알려진 NAN-190도 TFMPP의 작용을 차단하지 못하였으며 S(-)-propranolol도 영향을 미치지 않았다. 본 연구의 결과 중추 $5-HT_{1B}$수용체는 신장기능에 이뇨 및 Na배설 촉진적인 영향을 미치고 있고 이작용에 atrial natriuretic peptide가 관여함을 알 수 있었다.

• 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.

• Biomolecules & Therapeutics
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• 제4권1호
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• pp.7-18
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• 1996

5-Hydroxytryptamine(5-HT, serotonin), when given into the vein, produced antidiuretic action accompanied with reduction of glomerular filtration(GFR), renal plasma flow(RPF), osmolar clearance(Cosm) and amounts of sodium or potassium excreted in urine( $E_{Na}$ , $E_{K}$), with the augmented reabsorption rates of sodium and potassium in renal tubules. 5-HT, when infused into a renal artery, exhibited diuretic action accompanied with the augmented RPF and increased $E_{Na}$ and $E_{K}$ in only infused kidney. Antidiuretic action of 5-HT infused into the vein was not influenced by ketanserin, 5-H $T_2$receptor blockade, given into a renal artery, vein or carotid artery, by methysergide, 5-H $T_1$receptor blockade, given into a renal artery, whereas above antidiuretic action was inhibited by methysergide given into vein or carotid artery. Diuretic action of 5-HT infused into a renal artery in only experimental kidney was blocked by ketanserin injected into a renal artery, was not influenced by methysergide administered into a renal artery. Above results suggest that 5-hydroxytryptamine(5-HT) produced the antidiuretic action through central 5-H $T_1$receptor and the diuretic action through 5-H $T_2$receptor located in renal tubules of kidney.ney.

• The Korean Journal of Physiology and Pharmacology
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• 제23권4호
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• pp.271-279
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• 2019

The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current ($I_{Gly}$). Firstly, we examined with a $5-HT_1$ receptor agonist (8-OH-DPAT, $5-HT_{1/7}$ agonist, co-applied with SB-269970, $5-HT_7$ antagonist) and antagonist (WAY-100635), but $5-HT_1$ receptor agonist did not increase $I_{Gly}$ and in the presence of $5-HT_1$ antagonist, the potentiation of 5-HT on $I_{Gly}$ still happened. However, an agonist (${\alpha}$-methyl-5-HT) and antagonist (ketanserin) of the $5-HT_2$ receptor mimicked and inhibited the enhancing effect of 5-HT on $I_{Gly}$ in the SG neurons, respectively. We also verified the role of the $5-HT_7$ receptor by using a $5-HT_7$ antagonist (SB-269970) but it also did not block the enhancement of 5-HT on $I_{Gly}$. Our study demonstrated that 5-HT facilitated $I_{Gly}$ in the SG neurons of the Vc through the $5-HT_2$ receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.

• 대한약리학회지
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• 제28권1호
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• pp.19-25
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• 1992

Nonbenzodiazepine계 항불안제인 buspirone을 이용하여 건강한 8명의 남자를 대상으로 prolactin과 cortisol분비를 측정하였다. Buspirone는 $Dopamine_2$ 수용체 antagonist 성질 뿐 아니라 $5-HT_{1A}$ partial agonist 효과가 있는 것으로 보고되고 있다. Buspirone 30mg 경구투여시 혈청 prolactin 농도는 유의한 증가를 보였으나 혈청 cortisol 농도의 변화는 차이가 없었다. beta adrenoreceptor antagonist이면서 $5-HT_{1A}$ 수용체 antagonist로 알려진 pindolol (30mg)을 경구 투여한 결과 기초 혈청 prolactin이나 cortisol 농도는 유의한 차이가 없었다. Pinodlol을 전처치한 경우 buspirone-induced prolaction 분비의 유의한 억제효과는 없었다. 이상의 성적은 buspirone-induced prolactin 분비증가는 아마도 $5-HT_{1A}$ 수용체 활성과 관련되지 않음을 시사하는 것으로 사료된다.