• 제목/요약/키워드: Dopamine receptor ligand

검색결과 10건 처리시간 0.028초

Molecular Modeling of the Subtype Dopamine Receptor-ligand Interactions

  • Baek, Minkyung;Shin, Woong-Hee
    • EDISON SW 활용 경진대회 논문집
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    • 제2회(2013년)
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    • pp.13-24
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    • 2013
  • Dopamine agonists and antagonists and its receptor play a critical role in the information transfer in the nervous system, and dopamine receptor-ligands interactions are deeply related to Parkinson's disease, schizophrenia and some other mental diseases. However, the only experimental 3D structure available for dopamine receptors is human D3 dopamine receptor. Therefore, it is important to create model of subtype dopamine receptor-ligands interactions. We report here the 3D structures of the human D1 and D2 dopamine receptor predicted by using GalaxyTBM, and its predicted binding site determined by using GalaxyDock. The highly conserved Asp on TM 3 and Phe on TM 6 have critical role in ligand binding. Also, highly conserved serines on TM 5 are essential for binding agonists and some kinds of antagonists. We identify differences between binding sites of agonists and antagonists of human D1 and D2 dopamine receptor, and find the reasons of selective binding of antagonists.

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Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors

  • Paudel, Suresh;Kim, Eunae;Zhu, Anlin;Acharya, Srijan;Min, Xiao;Cheon, Seung Hoon;Kim, Kyeong-Man
    • Biomolecules & Therapeutics
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    • 제29권4호
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    • pp.392-398
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    • 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.

상동성 모델링을 이용한 Tricyclic Isoxazole 유도체와 ${\alpha}_{2c}$-Adrenoceptor의 상호작용 (Interactions of Tricyclic Isoxazole Analogues with ${\alpha}_{2c}$-Adrenoceptor by Homology Modeling)

  • 최경섭;강나나;명평근;성낙도
    • 약학회지
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    • 제54권4호
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    • pp.300-308
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    • 2010
  • Adrenoceptor has been considered to be an important target in psychiatric disorders. Based on x-ray structures of bovine rhodopsin, we established homology model of ${\alpha}_{2c}$-adrenoceptor (ADA2C_rat) and then analyzed docking from binding model of receptor-ligand complex with high-active compound No.29 in tricyclic isoxazole analogues (1-30). We observed that the N (1.907 $\AA$) and O (1.712 $\AA$) atoms of isoxazole ring on the docked ligand (No.29) formed H-bonding interaction with O-H of Ser5.32 and carmeron phenyl ring centroid of tricyclic isoxazole formed $\pi-\pi$ interaction at 3.342 $\AA$ distance with phenyl ring centroid of Phe6.52. According to predictions of blood-brain distribution (logBB) through penetration of blood-brain barrie (BBB) and polar surface area (PSA) of the ligands, the high-active compound No.29 has values of logBB=-0.203, PSA=67.50, respectively. These results suggest that the high-active compound No.29 is a novel anti-depressant with the characteristics such as dopamine and serotonin.

Anti-stress effects of ginseng via down-regulation of tyrosine hydroxylase (TH) and dopamine ${\beta}$-hydroxylase (DBH) gene expression in immobilization-stressed rats and PC12 cells

  • Kim, Yang-Ha;Choi, Eun-Ha;Doo, Mi-Ae;Kim, Joo-Yeon;Kim, Chul-Jin;Kim, Chong-Tai;Kim, In-Hwan
    • Nutrition Research and Practice
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    • 제4권4호
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    • pp.270-275
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    • 2010
  • Catecholamines are among the first molecules that displayed a kind of response to prolonged or repeated stress. It is well established that long-term stress leads to the induction of catecholamine biosynthetic enzymes such as tyrosine hydroxylase (TH) and dopamine ${\beta}$-hydroxylase (DBH) in adrenal medulla. The aim of the present study was to evaluate the effects of ginseng on TH and DBH mRNA expression. Repeated (2 h daily, 14 days) immobilization stress resulted in a significant increase of TH and DBH mRNA levels in rat adrenal medulla. However, ginseng treatment reversed the stress-induced increase of TH and DBH mRNA expression in the immobilization-stressed rats. Nicotine as a ligand of the nicotinic acetylcholine receptor (nAChR) in adrenal medulla stimulates catecholamine secretion and activates TH and DBH gene expression. Nicotine treatment increased mRNA levels of TH and DBH by 3.3- and 3.1-fold in PC12 cells. The ginseng total saponin exhibited a significant reversal in the nicotine-induced increase of TH and DBH mRNA expression, decreasing the mRNA levels of TH and DBH by 57.2% and 48.9%, respectively in PC12 cells. In conclusion, immobilization stress induced catecholamine biosynthetic enzymes gene expression, while ginseng appeared to restore homeostasis via suppression of TH and DBH gene expression. In part, the regulatory activity in the TH and DBH gene expression of ginseng may account for the anti-stress action produced by ginseng.

N-(4-[$^{18}F$Fluoromethylbenzyl)spiperone : 유력한 도파민 $D_2$ 수용체 선택성 방사성리간드 (N-(4-[$^{18}F$]Fluoromethylbenzyl)spiperone : A Selective Radiotracer for In Vivo Studies of Dopamine $D_2$ Receptors)

  • 김상은;최연성;지대윤;이경한;최용;김병태
    • 대한핵의학회지
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    • 제31권4호
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    • pp.421-426
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    • 1997
  • [$^{18}F$]FMBS는 도파민 $D_2$ 수용체 방사성추적자로서 유망한 성질을 지니고 있다. [$^{18}F$]FMBS는 비교적 높은 특이결합/비특이결합 비를 제공하며, 그 체내결합은 도파민 $D_2$ 수용체에 대하여 높은 특이성과 선택성을 보인다. 도파빈 $D_2$ 수용체 측정을 위한 보다 적합한 PET 방사성추적자를 얻기 위해서는 [$^{18}F$]FMBS의 낮은 뇌섭취와 느린 역학을 개선할 수 있는 화학적 구조의 변형이 시도되어야 하며, [$^{18}F$]FMBS는 이러한 시도의 골격이 될 수 있을 것으로 믿는다.

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Imaging Neuroreceptors in the Living Human Brain

  • Wagner Jr Henry N.;Dannals Robert F.;Frost J. James;Wong Dean F.;Ravert Hayden T.;Wilson Alan A.;Links Jonathan M.;Burns H. Donald;Kuhar Michael J.;Snyder Solomon H.
    • 대한핵의학회지
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    • 제18권2호
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    • pp.17-23
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    • 1984
  • For nearly a century it has been known that chemical activity accompanies mental activity, but only recently has it been possible to begin to examine its exact nature. Positron-emitting radioactive tracers have made it possible to study the chemistry of the human mind in health and disease, using chiefly cyclotron-produced radionuclides, carbon-11, fluorine-18 and oxygen-15. It is now well established that measurable increases in regional cerebral blood flow, glucose and oxygen metabolism accompany the mental functions of perception, cognition, emotion and motion. On May 25, 1983 the first imaging of a neuroreceptor in the human brain was accomplished with carbon-11 methyl spiperone, a ligand that binds preferentially to dopamine-2 receptors, 80% of which are located in the caudate nucleus and putamen. Quantitative imaging of serotonin-2, opiate, benzodiazapine and muscarinic cholinergic receptors has subsequently been accomplished. In studies of normal men and women, it has been found that dopamine and serotonin receptor activity decreases dramatically with age, such a decrease being more pronounced in men than in women and greater in the case of dopamine receptors than serotonin-2 receptors. Preliminary studies in patients with neuropsychiatric disorders suggests that dopamine-2 receptor activity is diminished in the caudate nucleus of patients with Huntington's disease. Positron tomography permits quantitative assay of picomolar quantities of neuro-receptors within the living human brain. Studies of patients with Parkinson's disease, Alzheimer's disease, depression, anxiety, schizophrenia, acute and chronic pain states and drug addiction are now in progress. The growth of any scientific field is based on a paradigm or set of ideas that the community of scientists accepts. The unifying principle of nuclear medicine is the tracer principle applied to the study of human disease. Nineteen hundred and sixty-three was a landmark year in which technetium-99m and the Anger camera combined to move the field from its latent stage into a second stage characterized by exponential growth within the framework of the paradigm. The third stage, characterized by gradually declining growth, began in 1973. Faced with competing advances, such as computed tomography and ultrasonography, proponents and participants in the field of nuclear medicine began to search for greener pastures or to pursue narrow sub-specialties. Research became characterized by refinements of existing techniques. In 1983 nuclear medicine experienced what could be a profound change. A new paradigm was born when it was demonstrated that, despite their extremely low chemical concentrations, in the picomolar range, it was possible to image and quantify the distribution of receptors in the human body. Thus, nuclear medicine was able to move beyond physiology into biochemistry and pharmacology. Fundamental to the science of pharmacology is the concept that many drugs and endogenous substances, such as neurotransmitters, react with specific macromolecules that mediate their pharmacologic actions. Such receptors are usually identified in the study of excised tissues, cells or cell membranes, or in autoradiographic studies in animals. The first imaging and quantification of a neuroreceptor in a living human being was performed on May 25, 1983 and reported in the September 23, 1983 issue of SCIENCE. The study involved the development and use of carbon-11 N-methyl spiperone (NMSP), a drug with a high affinity for dopamine receptors. Since then, studies of dopamine and serotonin receptors have been carried out in over 100 normal persons or patients with various neuropsychiatric disorders. Exactly one year later, the first imaging of opitate receptors in a living human being was performed [1].

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Anew formula CPC22 regulates bone loss, hot flashes, and dysregulated lipid metabolism in ovariectomized postmenopausal mice

  • Hee-Yun Kim;Hyunwoo Jee;Hosong Cho;Dongjun Park;Hyun-Ja Jeong
    • 셀메드
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    • 제13권14호
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    • pp.15.1-15.15
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    • 2023
  • Background and objective: A new formular CPC22 consists of Cynanchum wilfordii root, Pueraria thomsonii flower, and Citrus unshiu peel and has been developed to improve the postmenopausal symptoms. The research intended to evaluate whether CPC22 would regulate bone loss, hot flashes, and dysregulated lipid metabolism in ovariectomized (OVX) postmenopausal mice. Method: The OVX mice were orally administered with CPC22 daily for 7 weeks. Results: CPC22 regulated OVX-induced bon loss by enhancing serum osteoprotegerin, alkaline phosphatase, and osteocalcin levels and diminishing serum receptor-activator of the NF-κB ligand (RANKL), collagen type 1 cross-linked N-telopeptide, and tartrate-resistant acid phosphatase levels. As a result of CPC22 treatment, notable decreases in tail skin temperature and rectal temperature were observed, along with diminishment in hypothalamic RANKL and monoamine oxidase A levels and enhancement in hypothalamic serotonin (5-HT), norepinephrine, dopamine, 5-HT2A, and estrogen receptor-β levels. CPC22 enhanced levels of serum estrogen and diminished levels of serum follicle-stimulating hormone and luteinizing hormone. CPC22 regulated levels of serum lipid metabolites, including total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Furthermore, CPC22 diminished levels of serum blood urea nitrogen, creatine kinase, alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase and restored vaginal dryness without affecting uterus atrophy index and vagina weights. Conclusion: Therefore, these results indicated that CPC22 improves OVX-induced bone loss, hot flashes, and dysregulated lipid metabolism by compensating for estrogen deficiency without side effects, suggesting that CPC22 may be used for the prevention and treatment of post menopause.

소동물에서 18F-Fallypride의 비방사능에 따른 뇌의 PET이미지와 Binding Potential 차이에 대한 연구 (A study of Brain Micro-PET Imaging and Bindingpotential with a Different Specific Activity of 18F-Fallypride in the Small Animal)

  • 조규상;안성민
    • 한국콘텐츠학회논문지
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    • 제15권9호
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    • pp.418-424
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    • 2015
  • 본 연구에서는 비방사능 값에 따른 소동물 in vivo실험에서 어느 정도의 비방사능에서부터 수용체-리간드의 결합능력의 변화와 선조체에서의 방사능 집적에 변화가 있는지를 규명하고자 실험을 진행하다. 18F-Fallypride을 3가지 값 ; 높은 비방사능 : 43.29~74 GBq/umol, 중간 비방사능 : 20.72~29.23 GBq/umol, 낮은 비방사능 : 6.29~8.51 GBq/umol)으로 나누어 순차적으로 혈관주사 후 Micro PET을 이용하여 90분 동적 스캔 하였다. 스캔 후 양쪽 선조체에서 Binding Potential(BP)을 구한 후 비교 분석하였다. 높은 비방사능과 낮은 비방사능, 중간 비방사능과 낮은 비방사능에서 유의한 차이가 나타났다. 또한 18F-Fallypride을 이용한 PET 영상비교에서는 높은 비방사능과 중간 비방사능에서는 선조체 에서 높은 방사능집적을 보여주었지만, 낮은 비방사능에서는 다른 두 비방사능에 비해 낮은 방사능 집적을 볼 수 있었다. 이는 18F-Fallypride의 약동학적 특성상 D2/D3에 대한 친화성이 좋기 때문에 비방사능 값이 어느 정도 떨어진 상태에서도 BP의 차이가 크지 않았다. 하지만 높은 비방사능에 비해 6.5배 낮은 비방사능 값 부터는 이미지 및 BP의 차이가 유의하게 나왔으므로 앞으로 18F-Fallyprdie을 이용한 선조체 PET연구에서는 이를 고려하여 실험 할 필요가 있을 것이다.