• Biomolecules & Therapeutics
• /
• v.29 no.4
• /
• pp.392-398
• /
• 2021

In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure-activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotonin/norepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D₂ receptor (D₂R) significantly inhibited DA-induced endocytosis of D₂R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D₂R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D₂R function.

• Korean Journal of Pharmacognosy
• /
• v.25 no.2
• /
• pp.167-170
• /
• 1994

The platelet activating factor (PAF) is a newly discovered chemical mediator, the chemical structure of which is 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. Since PAF has potent and broad activities, its pathophysiological roles have received much attention. To develope a new PAF antagonist from medicinal plants, extracts of twenty medicinal herb were screened using PAF receptor binding, $[^{14}C]$ serotonin release and platelet aggregation.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.27 no.2
• /
• pp.225-232
• /
• 2013

Delayed gastrointestinal (GI) motility is frequent adverse effect associated with chemotherapy, and induced by serotonin releases from enterochromaffin cells. Ijintang-gamibang (IJG) is a digestive polyherbal formula has been traditionally used in Korea and consisted of 8 types of medicinal herbs. This study was conducted to determine whether or not IJG aqueous extracts can prevent delayed GI motility induced by the antineoplastic drug cisplatin chronically administered, once per week for five consecutive weeks (2 mg/kg). 200, 100 and 50 mg/kg of IJG extracts were orally administered, once a day for 14 days from fourth cisplatin treatment, and the changes in body weight gain, fecal parameters, gastrointestinal transit ratio and histopathology were observed. In addition, pylorus gastrin and serotonin contents were also measured with immunohistochemical observations of enterochromaffin cells contains gastrin and serotonin, as compared with ondansetron, a serotonin 5-HT3 receptor antagonist, 1 mg/kg. Cisplatin treatment related body weight decreases, delayed GI motility, decreases of fecal water contents were significantly and dose-dependently inhibited by oral treatment of IJG extracts, and they also inhibited the pylorus gastrin and serotonin changes induced by cisplatin treatment. The overall effects of IJG 100 mg/kg were similar to that of ondansetron 1 mg/kg. The present results supported that IJG aqueous extracts have favorable ameliorating effect on the delayed GI motility induced by chemotheraphy, modulated the GI enterochromaffin cells, serotonin and gastrin-producing cells with antioxidant effects. This effect of IJG may help improve accompanying gastrointestinal symptoms by chemotherapy.

• Biomolecules & Therapeutics
• /
• v.18 no.3
• /
• pp.246-256
• /
• 2010

Atopic dermatitis is a common skin disease affecting up to 10% of children and approximately 2% of adults. Atopic dermatitis exhibits four major symptoms, including intense itching, dry skin, redness and exudation. The "itch-scratch-itch" cycle is one of the major features in atopic dermatitis. The pathophysiology and neurobiology of pruritus is unclear. Currently there are no single and universally effective pharmacological antipruritic drugs for treatment of atopic dermatitis. Thus, controlling of itch is a very important unmet need in patients suffering from atopic dermatitis. This article will update progress during the past 10 years of research in the field of pruritus of atopic dermatitis, focusing on aspects of pruritogens (including inflammatory lipids, histamine, serotonin, proteinases, proteinase-activating receptors, neurotransmitters, neuropeptides, and opioid peptides), antipruritic therapies, and emerging new targets. Based on recent progress, researchers expect to identify exciting possibilities for improved treatments and to develop new antipruritic drugs acting through novel targets, such as histamine H4 receptor, gastrin-releasing peptide receptor, MrgprA3, thromboxane A2 receptor and the putative SPC receptor.

• The Korean Journal of Physiology and Pharmacology
• /
• v.19 no.6
• /
• pp.523-531
• /
• 2015

Serotonin [5-hydroxytryptamine (5-HT)] regulates synaptic plasticity in the visual cortex. Although the effects of 5-HT on plasticity showed huge diversity depending on the ages of animals and species, it has been unclear how 5-HT can show such diverse effects. In the rat visual cortex, 5-HT suppressed long-term potentiation (LTP) at 5 weeks but enhanced LTP at 8 weeks. We speculated that this difference may originate from differential regulation of neurotransmission by 5-HT between the age groups. Thus, we investigated the effects of 5-HT on apha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-, ${\gamma}$-aminobutyric acid receptor type A (GABAAR)-, and N-methyl-D-aspartic acid receptor (NMDAR)-mediated neurotransmissions and their involvement in the differential regulation of plasticity between 5 and 8 weeks. AMPAR-mediated currents were not affected by 5-HT at both 5 and 8 weeks. GABAAR-mediated currents were enhanced by 5-HT at both age groups. However, 5-HT enhanced NMDAR-mediated currents only at 8 weeks. The enhancement of NMDAR-mediated currents appeared to be mediated by the enhanced function of GluN2B subunit-containing NMDAR. The enhanced GABAAR- and NMDAR-mediated neurotransmissions were responsible for the suppression of LTP at 5 weeks and the facilitation of LTP at 8 weeks, respectively. These results indicate that the effects of 5-HT on neurotransmission change with development, and the changes may underlie the differential regulation of synaptic plasticity between different age groups. Thus, the developmental changes in 5-HT function should be carefully considered while investigating the 5-HT-mediated metaplastic control of the cortical network.

• The Korean Journal of Pharmacology
• /
• v.29 no.2
• /
• pp.189-193
• /
• 1993

Exposure of dissociated cultures from fetal rat brainstem to glutamate for upto 6 h decreased cellular contents of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in a concentration- and time-dependent manner. In addition, glutamate induced lactate dehydrogenase leakage. Tetrodotoxin did not block the effects induced by glutamate. MK-801 $(1{\mu}M)$, an N-methyl-D-aspartate (NMDA) channel blocker, but not 6-cyano-2,3-dihydroxy-7-nitro-quinoxazoline $(CNQX;\;3{\mu}M)$, a non-NMDA receptor antagonist, blocked glutamate-induced effects, indicating that these glutamate-induced responses are mediated through NMDA receptors.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1992.05a
• /
• pp.39-39
• /
• 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.

• Tuberculosis and Respiratory Diseases
• /
• v.46 no.6
• /
• pp.811-816
• /
• 1999

Background : Nausea and vomiting associated with chemotherapy are common side effects which remain difficult to control. Acute phase nausea and vomiting (0-24 hours after induction of chemotherapy) parallels plasma serotonin release, which explains the effectiveness of $5-HT_3$ receptor antagonists. Serotonin released from gastrointestinal enterochromaffin cells may mediate chemotherapy-induced emesis. In this study, we analyzed urinary excretion of 5-HIAA, the main metabolite of serotonin. Methods : Eight men and four women were studied in their cisplatin chemotherapy cycle. Urinary 5-hydroxyindoleaoetic aicd (HIAA) levels were determined before and during a 24-hour period under ondansetron prophylaxis. Results : Urinary 5-HIAA excretion for a 24-hour period was increased in all patients after induction of cisplatin (P=0.002). Conclusion : Cisplatin chemotherapy is associated with serotonin release in the acute phase. Our finding may provide evidence for a relationship between emesis and serotonin following cisplatin chemotherapy.

• Korean Journal of Biological Psychiatry
• /
• v.6 no.1
• /
• pp.3-11
• /
• 1999

At the beginning, researches on the biology of depression or affective illness have focused mainly on the receptor functions and neuroendocrine activities. And the studies of the past years did not break new theoretical background, but the recent advances in the research on the molecular mechanisms underlying neural communication and signal transduction do add some insights to many established ideas. This article will overview some of the more recent advances in the clinical researches of depression. Our major concerns to be presented here include the followings : (1) alterations in the post-synaptic neural transduction ; (2) changes in the neurons of hypothalamic neuropeptides ; (3) decreased peptidase enzyme activities ; (4) associations of hypothalamic-pituitary-adrenal axis abnormalities with serotonin neurotransmission ; (5) role of serotonin transporter ; (6) changes in the responsiveness of intracellular calcium ion levels ; (7) the inositol deficiency theory of lithium and depression ; (8) the transcription factors including immediate early genes ; (9) recent genetic studies in some families. This brief overview will suggest that changes in DNA occur during antidepressant therapy. These changes at the DNA level initiating a cascade of events underlying antidepressant modality will give us the insights on the molecular biological basis of the pathogenesis of depression and cues for a new class of antidepressants.

• The Journal of Pediatrics of Korean Medicine
• /
• v.36 no.3
• /
• pp.87-96
• /
• 2022

Objective The purpose of this study was to confirm the effect of Sabaek-san extract on skin damage recovery and inflammation relief in atopic dermatitis-induced mice through Endocannabinoid system (ECS) control. Methods In this study, we used 6-week-old NC/Nga mice were divided into 4 group: control group (Ctrl), lipid barrier elimination group (LBEG), palmitoylethanolamide (PEA) treated group after lipid barrier elimination (PEAG), and Sabaek-san extract treatment group after lipid barrier elimination (SBSG). Each group was assigned 10 animals. After drug administration of three weeks duration following lipid barrier elimination, cannabinoid receptor (CB) 1, CB2, CD (Cluster of Differentiation) 68, phosphorylated inhibitor kappa B (p-IκB), inducible nitric oxide synthase (iNOS), Fc ε receptor, substance P and serotonin were observed to confirm the regulation of the ECS, macrophage activity and mast cell activity. Results We found that 8-hydroxydeoxyguanosine (8-OXdG) positive reaction was significantly lower in the SBST group than in LBET and PEAT groups. Both CB1 and CB2 showed higher positive reactions in the SBST group than in the LBET and PEAT. CD68, p-IκB, iNOS, Fc ε receptor, Substance P and serotonin showed lower positive reaction in the SBST compared to the LBET and PEAT. Conclusion It was confirmed that the Sabaek-san extract can reduce the inflammation of atopic dermatitis by restoring the structural damage of the skin lipid barrier through ECS activity.