N-Methyl Amine-substituted Fluoxetine Derivatives: New Dopamine Transporter Inhibitors

Young Sil Yoon,Taesup Cho,Sung-Hwa Yoon,Churl Ki Min,Changho Lee 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.12

Transport of dopamine (DA) by the dopamine transporter from the synaptic cleft into the presynaptic terminals plays a key role in terminating dopaminergic neurotransmission. The binding of psychostimulants to their recognition sites on the DA transporter leads to an inhibition of DA transport and a subsequent rising of the dopamine contents in the synaptic cleft is ascribed to a mode of psychostimulation. Discovery of dopamine transporter inhibitors would be useful with regard to substituting for cocaine and minimizing its abuse. Recently, a number of fluoxetine analogues were synthesized, especially focusing on the substitution of N-methyl amine group through modifying the structure of the fluoxetine, N-methyl-3-[p-trifluoromethylphenoxy]-3-phenylpropylamine, widely used as an antidepressant. Among them, the pharmacological properties of FD-2, (R)-N-ethanol-3-(4-trifluorophenoxy)-3-phenyl propaneamine and FD-4, N-(R)-3-trifluorophenoxy-3-phenylpropane-imidazole with a higher affinity for the DA transporter were characterized in terms of dopamine transporter inhibition expecting for useful cocaine substitutes. Effects of the compounds on [H3]dopamine uptake, [I125]RTI-55 binding, and DA transporter-associated currents were examined with the ligand binding assays and voltage clamping technique in human embryonic kidney (HEK)-293 cells where the recombinant human DA transporter (hDAT) was stably expressed. Our results showed that (i) fluoxetine was potent in inhibiting both the uptake of [H3]DA (IC50 = 0.21 ± 0.032 mM, n = 3) and the [I125]RTI-55 binding (IC50 = 0.23 ± 0.012 mM, n = 10); (ii) N-methyl amine substituted fluoxetine analogues, FD-2 and FD-4 were equally or more potent than fluoxetine itself in terms of inhibition of [H3]DA uptake (IC50 FD-2: 0.077 ± 0.0032 mM (n = 3); FD-4: 0.26 ± 0.13 mM (n = 3), inhibition of [I125]RTI-55 binding, and reduction in DA transporter-associated currents, suggesting that these analogues could be a new class of dopamine transporter inhibitors.

Drug-Native Tourette 장애 아동에서 [123I] IPT SPECT로 측정한 기저 신경절 Dopamine Transporter Density 양상

천근아,유영훈 대한신경정신의학회 2002 신경정신의학 Vol.41 No.4

연구목적: 뚜렛 장애가 기저 신경절 presynaptic dopamine 신경계의 기능 이상으로 인한 dopamine 과잉분 포와 연관이 있다는 증거는 많다. 본 연구는 Dopamine transporter density가 dopamine 신경 말단 의 dopamine의 농도와 비례한다는 전제하에 Dopamine transporter density 영상을 보는 I-123- IPT brain SPECT를 이용하여, 약물 비노출(drug-naive) 뚜렛 장애 아동에서 기저 신경절 Dop􀀐 amine transporter density 양상을 알아보고자 하였다. 또한 뚜렛 장애의 틱증상 심각도와 Dopamine transporter density와의 연관성을 알아보고자 하였다. 방 법: 연구대상은 8명의 뚜렛 장애 아동(mean age=9.75±1.98세)과 6명의 정상 대조군(mean age=10.33 ±2.88세)이었다. 8명의 뚜렛 장애 아동 모두 이전에 틱증상 억제 약물을 투여받은 적이 없는 약물- 비노출 상태였다. 뚜렛 장애군과 정상 대조군 모두를 대상으로 I-123 IPT를 정맥주사 후 2시간 후 에 SPECT를 촬영하였으며 그 영상을 분석하여 좌, 우측의 기저 신경절의 특이결합/비특이결합 비율 을 구한 후, 각 군간의 차이를 정량적으로 분석하였다. 뚜렛 장애 아동의 틱증상과 Dopamine tra􀀐 nsporter density와의 연관성을 알아보기 위하여 YGTSS로 측정한 틱증상 총점과 좌, 우측 기저 신 경절 특이결합/비특이결합 비율의 상관관계를 알아보았다. 결 과: 약물 비노출(drug-naive) 뚜렛 장애 아동(n=8)과 정상 아동(n=6)의 좌, 우측의 기저신경절의 특이 결합/비특이결합 비율을 비교해 본 결과 우측 기저 신경절의 특이결합/비특이결합 비율에서는 유의한 차이가 없었다. 그러나 좌측 기저 신경절의 특이결합/비특이결합 비율에서는 약물 비투여 뚜렛 장애 아동군이 정상 아동군보다 유의하게 높은 것으로 나타났다(z=-2.453, p=0.013). 뚜렛 장애 아동의 틱증상 심각도와 좌, 우측 기저 신경절 특이결합/비특이결합 비율과의 상관관계에서는 유의한 연관성 을 보이지 않았다. 결 론: 뚜렛 장애 아동군이 정상 아동군에 비하여 좌측 기저 신경절의 Dopamine transporter density가 유의하게 증가되어 있는 것을 알 수 있었다. 이러한 결과는 뚜렛 장애의 병태생리와 연관된 기저 신 경절 presynaptic dopamine 기능 이상으로 인한 dopamine 과잉 분포에 대한 가설을 지지한다고 볼 수 있다

Classic Studies on the Interaction of Cocaine and the Dopamine Transporter

Vivek Verma 대한정신약물학회 2015 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.13 No.3

The dopamine transporter is responsible for recycling dopamine after release. Inhibitors of the dopamine transporter, such as cocaine, will stop the reuptake of dopamine and allow it to stay extracellularly, causing prominent changes at the molecular, cellular, and behavioral levels. There is much left to be known about the mechanism and site(s) of binding, as well as the effect that cocaine administration does to dopamine transporter-cocaine binding sites and gene expression which also plays a strong role in cocaine abusers and their behavioral characteristics. Thus, if more light is shed on the dopamine transporter-cocaine interaction, treatments for addiction and even other diseases of the dopaminergic system may not be too far ahead. As today’s ongoing research expands on the shoulders of classic research done in the 1990s and 2000s, the foundation of core research done in that time period will be reviewed, which forms the basis of today’s work and tomorrow’s therapies.

Antipsychotics and dopamine transporter gene polymorphisms in delirium patients

KIM, JEE-YEON,JUNG, IN-KWA,HAN, CHANGSU,CHO, SOOK-HAENG,KIM, LEEN,KIM, SEUNG-HYUN,LEE, BUN-HEE,LEE, HEON-JEONG,KIM, YONG-KU Blackwell Science Pty 2005 Psychiatry and Clinical Neurosciences Vol.59 No.2

<P>Abstract </P><P>The main objective of the present study was to determine the relationship between treatment responses of delirium and genetic polymorphisms in the dopamine transporter. The optimal dosages of haloperidol and risperidone in the treatment of delirium were also investigated. Either haloperidol or risperidone was administered to delirium patients, and delirium symptoms were measured daily until remission. Variable number of tandem repeat (VNTR) polymorphisms of the dopamine transporter were determined using the polymerase chain reaction. Among 42 subjects, symptoms of delirium appeared a mean of 9.68 days after hospitalization. A majority of the subjects (83.3%) had the type 10/10 polymorphism. Dosages of haloperidol and risperidone at the day of recovery were 1.67 mg/day (SD = 1.32; range 0.5–2.5 mg/day) and 1.19 mg/day (SD = 1.14; range 0.5–5.0 mg/day), respectively. The mean drug response time was 8.5 days in the haloperidol group and 4.8 days in the risperidone group (no significant difference). The response rates at the 3rd and 7th days after medication did not differ with either the drug group or the dopamine transporter polymorphism. Relatively low doses of risperidone and haloperidol exhibited similar efficacies, and dopamine transporter polymorphisms do not appear to play a major role in the action of antipsychotics on delirium.</P>

도파민과 세로토닌 운반체 및 수용체 영상을 위한 방사선리간드

지대윤(Dae Yoon Chi) 대한핵의학회 2000 핵의학 분자영상 Vol.34 No.3

In the 1980s, techniques to image the human subjects in a rhree-dimensiona1 direction were developed, Two major techniques are SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) which allow the detector to detect a single photon or annihilation photons emitted from the subjects injected with radiopharmaceuticals. Since the latter two techniques can measure the density of receptors, enzymes and transporters in living human, it may be very important project to develop selective methods of labeling with radionuclides and to develop new radiopharmaceuticals. There has been a considerable interest in developing new compounds which specifically bind to dopamine and serotonin receptor and transporters, and it will be thus very useful to label those compounds with radionuclides in order to gain a better understanding in biochemical and pharmacological interactions in living human. This review rnentions the characteristics of radioligands for the imaging of dopamine and serotonin receptors and transporters. Although significant progress has been achieved in the development of new PET and SPECT ligands for in vivo imaging of those receptors and transporters, there are continuous needs of new diagnostic radioligands, (Korean J Nucl Med 2000;34:159-68)

Preparation of Dopamine Transporter-specific Antibodies Using Molecular Cloned Genes

Lee, Shee-Yong,Im, Suhn-Young,Kim, Kyeong-Man The Pharmaceutical Society of Korea 1999 Archives of Pharmacal Research Vol.22 No.3

Dopamine transporter (DAT) plays the most important role in terminating the actions of dopamines released into the synaptic cleft. DAT is also the target of various psychotropic drugs such as cocaine and amphetamine. In this study were prepared DAT-specific antibodies using the 2nd extracellular loop of rat DAT as an antigen. The 2nd extracellular loop of the rat DAT was expressed in bacterial as a fusion protein with glutathione-S-transferase, and injected ito rabbits to raise antibodies. Produced antibodies clearly recognized the rat DAT in ELISA, immunoblotting, and immumoprecipitation. As expected from the high sequence homology between the rat and human DAT, the antibodies raised for the rat DAT cross-reacted with the human DAT in the immunoblotting. Considering the specificity for DAT with wide range of applications such as ELISA, immunoblotting, and immunoprecipitation, these antibodies would be valuable tool for understanding the pharmacological actions of dopamine transporter and drug addition.

Amphetamine-induced ERM Proteins Phosphorylation Is through $PKC{\beta}$ Activation in PC12 Cells

Jeong, Ha-Jin,Kim, Jeong-Hoon,Jeon, Song-Hee The Korean Society of Pharmacology 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.4

Amphetamine, a synthetic psychostimulant, is transported by the dopamine transporter (DAT) to the cytosol and increases the exchange of extracellular amphetamine by intracellular dopamine. Recently, we reported that the phosphorylation levels of ezrin-radixin-moesin (ERM) proteins are regulated by psychostimulant drugs in the nucleus accumbens, a brain area important for drug addiction. However, the significance of ERM proteins phosphorylation in response to drugs of abuse has not been fully investigated. In this study, using PC12 cells as an in vitro cell model, we showed that amphetamine increases ERM proteins phosphorylation and protein kinase C (PKC) ${\beta}$ inhibitor, but not extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinases (PI3K) inhibitors, abolished this effect. Further, we observed that DAT inhibitor suppressed amphetamine-induced ERM proteins phosphorylation in PC12 cells. These results suggest that $PKC{\beta}$-induced DAT regulation may be involved in amphetmaine-induced ERM proteins phosphorylation.

Amphetamine-induced ERM Proteins Phosphorylation Is through PKCb Activation in PC12 Cells

Ha Jin Jeong,김정훈,Songhee Jeon 대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.4

Amphetamine, a synthetic psychostimulant, is transported by the dopamine transporter (DAT) to the cytosol and increases the exchange of extracellular amphetamine by intracellular dopamine. Recently, we reported that the phosphorylation levels of ezrin-radixin-moesin (ERM) proteins are regulated by psychostimulant drugs in the nucleus accumbens, a brain area important for drug addiction. However, the significance of ERM proteins phosphorylation in response to drugs of abuse has not been fully investigated. In this study, using PC12 cells as an in vitro cell model, we showed that amphetamine increases ERM proteins phosphorylation and protein kinase C (PKC) b inhibitor, but not extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinases (PI3K) inhibitors, abolished this effect. Further, we observed that DAT inhibitor suppressed amphetamine-induced ERM proteins phosphorylation in PC12 cells. These results suggest that PKCb-induced DAT regulation may be involved in amphetmaine-induced ERM proteins phosphorylation.

Amphetamine-induced ERM Proteins Phosphorylation Is through PKCb Activation in PC12 Cells

Ha Jin Jeong,Jeong-Hoon Kim,Songhee Jeon 대한생리학회-대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.5

Amphetamine, a synthetic psychostimulant, is transported by the dopamine transporter (DAT) to the cytosol and increases the exchange of extracellular amphetamine by intracellular dopamine. Recently, we reported that the phosphorylation levels of ezrin-radixin-moesin (ERM) proteins are regulated by psychostimulant drugs in the nucleus accumbens, a brain area important for drug addiction. However, the significance of ERM proteins phosphorylation in response to drugs of abuse has not been fully investigated. In this study, using PC12 cells as an in vitro cell model, we showed that amphetamine increases ERM proteins phosphorylation and protein kinase C (PKC) b inhibitor, but not extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinases (PI3K) inhibitors, abolished this effect. Further, we observed that DAT inhibitor suppressed amphetamine-induced ERM proteins phosphorylation in PC12 cells. These results suggest that PKCb-induced DAT regulation may be involved in amphetmaine-induced ERM proteins phosphorylation.

Recent Advances in the Pharmacology of Tardive Dyskinesia

Stanley N. Caroff 대한정신약물학회 2020 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.18 No.4

Tardive dyskinesia (TD) is a syndrome of abnormal involuntary movements that follows treatment with dopamine D2-receptor antagonists. Recent approval of vesicular monoamine transporter-2 (VMAT2) inhibitors offers hope for reducing the impact of TD. Although these drugs represent a significant advance in patient care and a practical step forward in providing relief for patients with TD, understanding of the pharmacology of TD that could inform future research to prevent and reverse TD remains incomplete. This review surveys evidence for the effectiveness of VMAT2 inhibitors and other agents in the context of theories of pathogenesis of TD. In patients for whom VMAT2 inhibitors are ineffective or intolerable, as well as for extending therapeutic options and insights regarding underlying mechanisms, a review of clinical trial results examined as experimental tests of etiologic hypotheses is worthwhile. There are still compelling reasons for further investigations of the pharmacology of TD, which could generate alternative preventive and potentially curative treatments. Finally, benefits from novel drugs are best realized within an overall treatment strategy addressing the condition and needs of individual patients.