• Proceedings of the PSK Conference
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• 2000.10a
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• pp.147.2-148
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• 2000

• Proceedings of the PSK Conference
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• 2002.04a
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• pp.123.1-123.1
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• 2002

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.108-115
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• 2023

Numerous psychotropic and addictive substances possess structural features similar to those of β-phenethylamine (β-PEA). In this study, we selected 29 β-PEA derivatives and determined their structure-activity relationship (SAR) to their ability to inhibit dopamine (DA) reuptake; conducted docking simulation for two selected compounds; and identified their potential functionals. The compounds were subdivided into arylethylamines, 2-(alkyl amino)-1-arylalkan-1-one derivatives and alkyl 2-phenyl-2-(piperidin-2-yl)acetate derivatives. An aromatic group, alkyl group, and alkylamine derivative were attached to the arylethylamine and 2-(alkyl amino)-1-arylalkan-1-one derivatives. The inhibitory effect of the compounds on dopamine reuptake increased in the order of the compounds substituted with phenyl, thiophenyl, and substituted phenyl groups in the aromatic position; compounds with longer alkyl groups and smaller ring-sized compounds at the alkylamine position showed stronger inhibitory activities. Docking simulation conducted for two compounds, 9 and 28, showed that the (S)-form of compound 9 was more stable than the (R)-form, with a good fit into the binding site covered by helices 1, 3, and 6 of human dopamine transporter (hDAT). In contrast, the (R, S)-configuration of compound 28 was more stable than that of other isomers and was firmly placed in the binding pocket of DAT bound to DA. DA-induced endocytosis of dopamine D₂ receptors was inhibited when they were co-expressed with DAT, which lowered extracellular DA levels, and uninhibited when they were pretreated with compound 9 or 28. In summary, this study revealed critical structural features responsible for the inhibition of DA reuptake and the functional role of DA reuptake inhibitors in regulating D₂ receptor function.

• YAKHAK HOEJI
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• v.45 no.2
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• pp.205-213
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• 2001

The dopaminergic receptors were consisted of two distinct subtypes, $D_1$and $D_2$, each having different function. The present study was attempted to investigate the effects of R(-)-2,10,11-trihydroxy-N-n-propylnoraporphine (TNPA), a dopamine $D_2$receptor agonist, on renal function in dog. TNPA (5.0~15.0 $\mu$g/kg), when given into the vein, produced a dose-dependently antidiuresis along with the decrease in osmolar clearance ( $C_{osm}$) and urinary excretion of sodium and potassium ( $E_{Na}$ , and $E_{K}$). It also increased reabsorption rates of sodium and potassium in renal tubules ( $R_{Na}$ , $R_{K}$) without any changes in glomerular filtration rate (GFR), renal plasma flow (RPF) and free water clearance ( $C_{H2o}$). TNPA (0.5~1.5 $\mu$g/kg/min) infused into a renal artery decreased urine flow both in the experimental and the control kidneys. TNPA (1.5~5.0 $\mu$g/kg) administered via the carotid artery also greatly exhibited antidiuresis even at intravenously ineffective doses. Changes of renal function by TNPA given into both the renal artery and the carotid artery were almost the same aspect to those induced by intravenous TNPA. These results obtained from the present study suggest that TNPA produces antidiuresis by increasing the reabsorption rates of electrolytes in renal tubules, mainly distal tubule, through changing of central function.unction.

• Archives of Pharmacal Research
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• v.29 no.10
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• pp.904-910
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• 2006

The inhibitory effects of paeonol, a major compound of Paeoniae radix, on the development of locomotor sensitization, conditioned place preference (CPP) and dopamine receptor supersensitivity induced by the repeated administration of morphine were investigated through behavioral experiments. A single administration of morphine produces hyperlocomotion. Repeated administration of morphine develops sensitization (reverse tolerance), a progressive enhancement of locomotion, which is used as a model for studying the drug-induced drug-seeking behaviors, and CPP, which is used as a model for studying drug reinforcement. Paeonol inhibited morphine-induced hyperlocomotion, sensitization and CPP. In addition, paeonol inhibited the development of postsynaptic dopamine receptors supersensitivity, which may be an underlying common mechanism that mediates the morphine-induced dopaminergic behaviors such as sensitization and CPP. Apomorphine (a dopamine agonist)-induced climbing behaviors also were inhibited by a single direct administration of paeonol. These results provide evidence that paeonol exerts anti-dopaminergic activity, and it is suggested that paeonol may be useful for the prevention and therapy of these adverse actions of morphine.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.88-93
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• 1994

The mechanisms controlling the intensity and duration of synaptic transmission are numerous. Once an action potential reaches a nerve terminal, the stored neurotransmitters are released in a quantum fashion into the synaptic cleft. At that point neurotransmitters can act on post-synaptic receptors to elicit an action on the post-synaptic cell or net at so-called auto-receptors that are located on the presynaptic side and which often regulate the further release of the neutotransmitter. Whereas the action of the neurotransmitter receptors is regulated by desensitization phenomenon, the major mechanism by which the intensity and duration of neurotransmitter action is presumably regulated by either its degradation or its removal from the synaptic cleft. In the central nervous system, specialized proteins located in fe plasma membrane of presynaptic terminals function to rapidly remove neurotransmitters from the synaptic cleft in a sodium chloride-dependent fashion. These proteins have been referred to as uptake sites or neurotransmitter transporters. Once taken up by the plasma membrane transporters, neurotransmitters are repackaged into secretory vesicles by distinct transporters which depend on a proton gradient.

• Biomolecules & Therapeutics
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• v.24 no.2
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• pp.115-122
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• 2016

Sleep, which is an essential part of human life, is modulated by neurotransmitter systems, including gamma-aminobutyric acid (GABA) and dopamine signaling. However, the mechanisms that initiate and maintain sleep remain obscure. In this study, we investigated the relationship between melatonin (MT) and dopamine D2-like receptor signaling in pentobarbital-induced sleep and the intracellular mechanisms of sleep maintenance in the cerebral cortex. In mice, pentobarbital-induced sleep was augmented by intraperitoneal administration of 30 mg/kg MT. To investigate the relationship between MT and D2-like receptors, we administered quinpirole, a D2-like receptor agonist, to MT- and pentobarbital-treated mice. Quinpirole (1 mg/kg, i.p.) increased the duration of MT-augmented sleep in mice. In addition, locomotor activity analysis showed that neither MT nor quinpirole produced sedative effects when administered alone. In order to understand the mechanisms underlying quinpirole-augmented sleep, we measured protein levels of mitogen-activated protein kinases (MAPKs) and cortical protein kinases related to MT signaling. Treatment with quinpirole or MT activated extracellular-signal-regulated kinase 1 and 2 (ERK1/2), p38 MAPK, and protein kinase C (PKC) in the cerebral cortex, while protein kinase A (PKA) activation was not altered significantly. Taken together, our results show that quinpirole increases the duration of MT-augmented sleep through ERK1/2, p38 MAPK, and PKC signaling. These findings suggest that modulation of D2-like receptors might enhance the effect of MT on sleep.

• The Korean Journal of Pharmacology
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• v.18 no.2
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• pp.103-117
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• 1982

In an effort to provide evidence as to the regulatory role of the central dopaminergic system on the renal function, the effects of centrally administered dopamine and its specific antagonist haloperidol were investigated. Haloperidol (HA) given intracerebroventricularly (i.c.v.) induced antidiuresis in doses of 15 and $50{\mu}g/kg$. With $15{\mu}g/kg$ sodium reabsorption in the tubules was increased, while with $50{\mu}g/kg$ free-water reabsorption was increased. However, a marked diuresis with increased sodium and potassium was observed with $150{\mu}g/kg$. Hemodynamic changes were not evident, indicating that the diuresis is of tubular origin. Dopamine (DA), on the other hand, produced antidiuresis when given i.c.v. in a dose-related fashion. With smaller doses of 5 and $15{\mu}g/kg$ the antidiuresis was related to increased reabsorption of sodium in the tubules, but higher doses of 50 and $150{\mu}g/kg$ the decreases in renal blood flow and glomerular filtration rate were evident in addition to the tubular action. After pretreatment with $150{\mu}g/kg$ HA, the effects of $15{\mu}g/kg$ DA was abolished, but the antidiuretic actions of 50 and $150{\mu}g/kg$ were not blocked, and the natriuretic diuretic action of HA was overcome and became inconspicuous. These observations indicate that the central dopaminergic system influences the renal function by producing antidiuresis, and HA elicits diuresis and natriuresis by competitively antagonizing DA specifically on the central dopaminegic receptors. The antidiuresis observed with smaller doses of HA can be best explained by the facts that there are more than two types of DA-receptors in the brain and that the presynaptic autoreceptors on the dopaminergic neurones which affect the dopamine release at the synapse are more sensitive than the postsynaptic receptors. Overall, these data provide an evidence indicating that the central dopaminergic system plays a role in the regulation of renal function in the rabbit.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2005.11a
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• pp.49-66
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• 2005

Panax ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized Morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. GTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, we hypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum ($\mu$-receptors) and mouse vas deferens($\delta$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H ($\kappa$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS Prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced cAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.2
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• pp.71-78
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• 2009

(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-$HT_{2A}$, Ki=0.61 nM, 5-$HT_{2C}$, Ki=20.7 nM) and dopamine ($D_2$, Ki=45.9 nM, $D_3$, Ki=42.1 nM) receptors with over $10\sim100$-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing ($ED_{50}$=0.93 mg/kg) and DOI-induced head twitch ($ED_{50}$=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine ($ED_{50}$=0.54 mg/kg) and the avoidance response ($ED_{50}$=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose ($ED_{50}$=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.