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IN conclusion, the data obtained in the present study indicate that quinpirole and 7-OH-DPAT, two D_3/2 dopamine receptor agonists, inhibit the spontaneous [~3H]-ACh efflux and this effect is competitively antagonized by haloperid...
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IN conclusion, the data obtained in the present study indicate that quinpirole and 7-OH-DPAT, two D_3/2 dopamine receptor agonists, inhibit the spontaneous [~3H]-ACh efflux and this effect is competitively antagonized by haloperidol and probably mediated through dopamine D_2 receptors.
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Aqueous, organic and alcoholic extracts of 163 Bolivian, Chinese and Pakistani medicinal plants were evaluated for their ability to inhibit the binding of radipligands selective for the Dl and D2 dopamine receptor subtypes express...
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Aqueous, organic and alcoholic extracts of 163 Bolivian, Chinese and Pakistani medicinal plants were evaluated for their ability to inhibit the binding of radipligands selective for the Dl and D2 dopamine receptor subtypes expressed in Sf9 cells. Based upon the results of the initial screen, 25 extracts were selected for further evaluation. Concentration-response competitive radioligand binding studies were performed to obtain IC_(50) values for the inhibition of the binding at Dl or D2 receptors by the selected extracts. The Dl :D2 receptor ratio of IC_(50) values for the extracts ranged from approximately two-fold selective for the Dl receptor to threefold selective for the D2 receptor. Dl and D2 dopamine receptors are known to be linked to the activation and inhibition of adenylyl cyclase activity, respectively. Therefore, the selected extracts were tested for the ability to either a) stimulate adenylyl cyclase activity using stably transfected HEK 293 cells expressing human Dl receptors (hDl-HEK) or b) inhibit forskolin-dependent stimulation of adenylyl cyclase activity in stably transfected HEK 293 cells expressing rat D2 dopamine receptors (rD2-HEK). Two extracts were found to stimulate adenylyl cyclase activity in hDl-HEK cells. However, similar results were observed when untransfected HEK cells were used, suggesting that the ability of these two extracts to increase cAMP levels in hDl-HEK cells was not mediated through a Dl-like dopamine receptor. While the majority of extracts did not have an effect on forskolin-dependent stimulation in rD2-HEK cells, six extracts were capable of inhibiting adenylyl cyclase activity in these cells. For five of these extracts, the inhibitory effect appeared to be dependent upon the expression of D2 receptors because no inhibitory effect was observed when untransfected HEK 293 cells were used. In summary, the results of this preliminary radioligand binding and functional activity screen of extracts from medicinal plants for pharmacologic activity at Dl and D2 dopamine receptors indicated that the majority of components capable of binding to the Dl and D2 dopamine receptor subtypes appeared to be essentially non-selective. While none of the selected extracts were found to have agonist activity at Dl receptors, several of the extracts exhibited inverse agonist activity at Dl dopamine receptors. Five of the extracts appeared to be agonists at D2 dopamine receptors. Therefore, several classes of extracts were identified which appeared to contained unique combinations of the following pharmacologic properties: Dl dopamine receptor antagonist, D2 dopamine receptor antagonist, Dl receptor inverse agonists and D2 receptor agonists. In addition, two of the extracts tested appeared to modulate adenylyl cyclase activity, but this activity did not appear to be mediated through activation of a dopamine receptor subtype.
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Dopamine (1) is a key neurotransmitter whose impact on pharmacological processes is mediated by a family of dopamine receptors designated D-1, D-2, D-3, D-4, and D-5. Various diseases and conditions such as schizophrenia, drug abu...
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Dopamine (1) is a key neurotransmitter whose impact on pharmacological processes is mediated by a family of dopamine receptors designated D-1, D-2, D-3, D-4, and D-5. Various diseases and conditions such as schizophrenia, drug abuse, depression, restless leg syndrome, Parkinson's disease (PD), and inflammatory diseases have been linked to aberrant D-3 activity. Herein, we report a series of novel D-3 ligands with improved solubility over our previous lead compound, MC25-41 (2).
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Dopamine (1) plays a key role in normal physiological pathways in both the central nervous system and the periphery. The physiological impact of this neurotransmitter is mediated through its interaction with family of G-protein-co...
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Dopamine (1) plays a key role in normal physiological pathways in both the central nervous system and the periphery. The physiological impact of this neurotransmitter is mediated through its interaction with family of G-protein-coupled receptors (GPCRs). These receptors are designated as D-1, D-2, D-3, D-4, and D-5 and divided into two sub-families, the D-1-like sub-family (D-1 and D-5) and D-2-like sub-family (D-2, D-3 and D-4) based on pharmacological properties, amino acid homology, and genetic organization. Aberrant D-3 activity has been linked to multiple diseases and conditions such as depression, schizophrenia, substance use disorder, inflammatory diseases, and Parkinson's disease (PD). As part of our on-going program focused on the identification of novel D-3 ligands, we have identified a novel series of 5-(4-arylpiperazin-1-yl)-N-quinolinyl-pentanamides that are high affinity ligands for this receptor. [GRAPHICS] .
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LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (K-i value 0.2nM) at human D3 dopamine receptors, (ii) >100-fold D3 versus D2 dopamine receptor subtype binding s...
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LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (K-i value 0.2nM) at human D3 dopamine receptors, (ii) >100-fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low-affinity binding (K-i>5000nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [H-3]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10-15min at 37 degrees C) and binds with high affinity to both human (K-d=0.06 +/- 0.01nM) and rat (K-d=0.2 +/- 0.02nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [H-3]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [H-3]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.
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AIM: To define roles of the third intracellular loop (IL_3) length of G-protein coupled receptors in conferring the specificity for receptor binding and G- protein coupling. METHODS: By polymerase chain reaction (PCR), the IL_3 of...
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AIM: To define roles of the third intracellular loop (IL_3) length of G-protein coupled receptors in conferring the specificity for receptor binding and G- protein coupling. METHODS: By polymerase chain reaction (PCR), the IL_3 of D_2 receptor was replaced with the counter part of AT_1 receptor which has the shortest loop among all G-protein coupled receptors. D_2/AT_1 receptor cDNA was then stably transfected into Chinese hamster ovary cells and a clone with high level expression was obtained for receptor binding and agonist-induced phosphatidylinositols (PI) turnover experiments. Comparing to the D_2 receptor, D_2/AT_1 chimeric receptor had lower affinities for all D_2 receptor antagonism tested (spiperone, haloperidol, (+)-butaclamol, chlopromazine, clozapine, trifluo- perdazine) and different affinity profiles to agonists (apomorphine, dopamine, quinpirole, bromo- criptine).
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AIM: To study the influence of dopamine (DA) receptor antagonists upon the rewarding property of dihydroetoryphine (DHE). METHODS: Conditioned place preference (CPP) paradigm was used to characterize the rewarding effect of DHE. D...
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AIM: To study the influence of dopamine (DA) receptor antagonists upon the rewarding property of dihydroetoryphine (DHE). METHODS: Conditioned place preference (CPP) paradigm was used to characterize the rewarding effect of DHE. DA receptor antagonists were injeted administered subcutaneously or peritoneally and microinjected into nucleus accumbens (NAcc). CONCLUSION: The D_1 (but not D_2) receptors in NAcc are crucial in the Mediation of the rewarding effect of DHE.
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(1)Exogenous DA, D_1 receptor agonist DKF 38393 and D_2 receptor ago- Nist LY 171555 reduced CCDPK Ⅱactivity in striatal Slices; Glu also inhibited CCPPKⅡactivity in a concen- Tration-dependent manner. NMDAⅡreceptor antagonist ...
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(1)Exogenous DA, D_1 receptor agonist DKF 38393 and D_2 receptor ago- Nist LY 171555 reduced CCDPK Ⅱactivity in striatal Slices; Glu also inhibited CCPPKⅡactivity in a concen- Tration-dependent manner. NMDAⅡreceptor antagonist MK-801 could antagonize the inhibitory effect of SKF 38393 and LY 171555 on the CCDPKⅡactivity. The interaction Between DA and Glu transmitter systems is found in the Regulation of the CCDPKⅡand PKA activities and cell Function in the striatum.
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The depletion of DA in the mPFC did not modif both the basal leve and the VTA- stimulated DA efflux in the Nac, but significantly facili- tated the AMP(20μmol.L~-1)-evoked DA efflux within the NAc. In indicates that the mPFC DA e...
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The depletion of DA in the mPFC did not modif both the basal leve and the VTA- stimulated DA efflux in the Nac, but significantly facili- tated the AMP(20μmol.L~-1)-evoked DA efflux within the NAc. In indicates that the mPFC DA efflux system is in- volved in the regulation of evoked DA release in the NAc. Besides, the AMP-evoked increase of the extra- Ed by SPD(10, 30 mmol.L~-1)microinjection into the mPFC, though this injection of SPD could not alter the response on DA release by the stimulation of the VTA. SPD is capable of enhancing the function of D_1 Receptors in the mPFC, by which if facilitates the inhibi- Tion of DA release in the NAc.
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We investigated the subcellular distribution of dopamine D_1, D_2 and D_5 receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. ...
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We investigated the subcellular distribution of dopamine D_1, D_2 and D_5 receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D_1 receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D_2 receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant membrane fractions, yet were not present in buoyant membranes. Most D_5 receptor immunoreactivity was distributed into the cytoplasmic fraction, failing to sediment at forces up to 300,000g, while the remainder was localized to detergent-soluble membranes in cortex. D_5 receptors were undetectable in detergent-resistant fractions or raft-like subdomains. Following daily cocaine administration for seven days, a significant portion of D_1 receptors translocated from detergent-resistant membranes to detergent-soluble membranes and the cytoplasmic fraction. The distributions of D_5 and D_2 receptor subtypes were not significantly altered by cocaine treatment. These data imply that D_5 receptors are predominantly cytoplasmic, D_2 receptors are diffusely distributed within the cell, whereas D_1 receptors are mostly localized to lipid rafts within the rat frontal cortex. Dopamine receptor subtype localization is susceptible to modulation by pharmacological manipulations that elevate synaptic dopamine, however the functional implications of such drug-induced receptor warrant further investigation.
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