Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.1.107 (DAT)
1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One patient with acute nonlymphocytic leukemia (ANLL) in remission was given intensive chemotherapy (DAT regimen) as late intensification treatment. Seven leukaphereses were performed during the period of marrow recovery following aplasia induced by the DAT regimen. High numbers of nucleated cells (7.8 X 10(8)/kg) and granulocyte-macrophage precursors (9.5 X 10(4)/kg) were collected and then cryopreserved and stored in liquid nitrogen. When he relapsed, the patient was treated with etoposide (600 mg/m2), cyclophosphamide (120 mg/kg), and total body irradiation (1000 rad), followed by the transfusion of thawed autologous leukocytes. The time to reach 0.5 X 10(9) granulocytes/liter and 50 X 10(9) platelets/liter was 16 and 35 days, respectively. This observation demonstrates that circulating hemopoietic stem cells are capable of complete hemopoietic reconstitution after marrow-ablative therapy with supralethal doses of chemoradiotherapy.
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PMID:Successful autologous transplantation with peripheral blood hemopoietic cells in a patient with acute leukemia. 287 Sep 36

Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K(i) values of N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.
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PMID:Synthesis and ligand binding of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4'-iodophenyl)nortropane and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-disubstituted phenyl)nortropane. New high-affinity and selective compounds for the dopamine transporter. 913 33

The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.
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PMID:Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors. 1073 54

6-Methoxylated and 8-oxygenated benztropines were prepared and evaluated for their DAT and SERT activity (binding and uptake inhibition). Methoxylation at the two-carbon bridge of benztropine produced a novel class of potent and selective DAT ligands. An interesting enantioselectivity was also observed for this new class of chiral benztropines. The inactivity of the 8-oxygenated analogues seems to point out that, unlike cocaine and its analogues, interactions of benztropine ligands with DAT may be strongly governed by the nitrogen atom.
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PMID:Effects of two-carbon bridge region methoxylation of benztropine: discovery of novel chiral ligands for the dopamine transporter. 1127 29

A series of novel N- and 3alpha-modified piperidine-based analogues of cocaine were synthesized and tested for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. N-Demethylation of trans-(+)-3alpha-piperidine-based ligands leads to improved activity at the SERT and NET and modest changes at the DAT. Replacement of the N-methyl group in trans-(+)-ester 1a with phenylalkyl groups leads to a modest 2.3-fold improvement in activity at the SERT (K(i) < or = 3.27 microM), insignificant changes at the NET, and a 3.5-fold loss in activity at the DAT (K(i) > or = 810 nM); however, such replacement in cis-(-)-ester 4, the more potent isomer of 1a, leads, in general, to a significant decrease in activity at all monoamine transporters (K(i) > 1 microM). Other N-modified ligands, including the ligands with polar groups incorporated in the N-alkyl substituent (3e-g) and ligands lacking the basic nitrogen (3i and 6d), show decreased activity at all monoamine transporters, though ligands 3e-g are similar in potency at the NET to 1a. N-Norester 2a, a possible metabolite of the lead compound 1a, and alcohol 1c, a compound with a 3alpha-substituent that is more stable to metabolism than 1a, were selected for further behavioral tests in animals. Alcohol 1c and ester 2a are similar in potency at the DAT to cocaine, ester 1a, and oxadiazole 1b, and both fully substitute for cocaine and have potency similar to that of cocaine in drug discrimination tests. Like cocaine, 1c increased locomotor activity (LMA) monotonically with time, whereas 2a produces biphasic effects consisting of initial locomotor depression followed by delayed locomotor stimulation. An interesting difference between cocaine, ester 1a, alcohol 1c, and N-norester 2a is that 1c and 2a are significantly longer acting in LMA tests. Although this result was anticipated for alcohol 1c, it is rather surprising for 2a which has an ester function susceptible to hydrolysis, a pathway of in vivo deactivation of cocaine and its ester analogues. The present results may have important implications for our understanding of the pharmacological mechanisms underlying the behavioral actions of cocaine and of the structural features needed for the design of the new leads in the discovery of a cocaine abuse medication.
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PMID:SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement. 1210 1

A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3alpha derivatives were found to be the most potent compounds with the 3alpha-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki = 12 nM) was slightly less potent than the 3alpha-analogue, while the 3beta-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3alpha-analogue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure-activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter.
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PMID:Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives. 1690 23

3-Aryltropanes have been widely explored for potential medications for remediation of cocaine abuse. Research has focused predominantly on 8-azatropanes and it is now well recognized that these compounds can be designed to manifest varied selectivity and potency for inhibition of the dopamine, serotonin, and norepinephrine uptake systems. We had reported that the 8-nitrogen atom present in the 3-aryltropanes is not essential for tropanes to bind to monoamine uptake systems. We demonstrated that compounds in which the amine had been exchanged for an ether or a thioether retained binding potency and selectivity. We have now designed bivalent compounds in which two tropane moieties are linked by an intervening chain. These 8-homo- and 8-heterotropane bivalent compounds allowed a search for adjacent tropane binding sites on the DAT as well as a further exploration of whether the binding sites for 8-azatropanes are the same as those for other 8-heterotropanes. A comparison of these compounds with their progenitor tropanes cast into doubt the existence of proximal binding sites on the DAT, and offered support for the existence of different binding sites for the 8-azatropanes compared with 8-oxa- and 8-thiatropanes. Indeed, 8-aza bivalent tropanes inhibited DAT with potency about 10-fold lower (DAT: IC50 = 31 nM) than their monovalent counterparts. Furthermore, bivalent ligands in which one or both of the tropanes was devoid of an amine suffered a further loss of inhibitory potency. We conclude that it is unlikely that there exist two tropane binding sites in close proximity to one another on either the DAT or SERT.
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PMID:The synthesis of bivalent 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters. 1805 32

There is growing evidence indicating that reactive nitrogen species (RNS) and reactive oxygen species (ROS) are a major contributor to the pathogenesis and progression of Parkinson's disease. Here we investigated whether edaravone (free radical scavenger), minocycline (inducible nitric oxide synthase, iNOS inhibitor), 7-nitroindazole (neuronal NOS, nNOS inhibitor), fluvastatin (endothelial NOS, eNOS activator) and pitavastatin (eNOS activator) can protect against MPTP neurotoxicity in mice under the same condition. The present study showed that 7-nitroindazole could protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletion. Our immunohistochemical study showed that TH (tyrosine hydroxylase) and DAT (dopamine transporter) immunoreactivity was decreased significantly in the striatum and substantia nigra 5 days after MPTP treatment. The administration of 7-nitroindazole showed a protective effect against the severe reductions in levels of TH and DAT immunoreactivity in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the remarkable loss of TH protein levels in the striatum 5 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant loss in TH protein levels in the striatum 5 days after MPTP treatment. On the other hand, GFAP (glial fibrillary acidic protein) immunoreactivity increased significantly in the striatum and substantia nigra, 5 days after MPTP treatment. 7-Nitroindazole ameliorated severe increases in number of GFAP immunoreactive astrocytes in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the increase of GFAP protein levels in the striatum 5 days after MPTP treatment. 7-Nitroindazole prevented a significant increase in the GFAP protein levels in the striatum 5 days after MPTP treatment. The present results indicate that 7-nitroindazole can protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletions. These findings demonstrate that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared to the production of ROS, the overexpression of iNOS and the modulation of eNOS. Thus, our findings provide strong evidence for neuroprotective properties of nNOS inhibitor in this animal model of Parkinson's disease.
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PMID:Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice. 1823 88

By using the regular water-quality indices and the terrestrial ecotoxicological methods of inhibiting seed germination and root elongation, the ecological risk of the DAT-IAT process for municipal wastewater treatment was assessed. The results of regular water-quality indices determination showed that COD and SS in treated wastewater by the DAT-IAT process could attain the National Integrated Wastewater Discharge Standard. Although NH4+-N could also meet the standard, most of nitrogen could not be removed out of the wastewater because of the N-form changing from NH4+-N to NO3(-)-N. Thus, the ecological risk of eutrophication could not successfully be reduced. The results based on the determination of ecotoxicological indices showed that IC50 of COD in wastewater from inflow water, DAT and effluent toxic to the germination of wheat seeds decreased gradually. The IC50 of the inhibitory rate of seed germination was 249.3 mg x L(-1), 165.3 mg x L(-1) and 161.2 mg x L(-1), respectively, and the IC50 of the inhibitory rate of root elongation was 257.6 mg x L(-1), 154.0 mg x L(-1) and 142.1 mg x L(-1), respectively. It thus revealed that the ecotoxicity of wastewater increased after treatment by the DAT-IAT process, which demanded more studies to address the regulation of the ecological risk. In particular, the inhibition of wheat root elongation was far more sensitive than the germination of wheat seeds under the same water-quality conditions. Thus, the root elongation could be recommended as a sensitive method to assess ecological risk of wastewater treatment effluents.
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PMID:[Ecological risk assessment of the DAT-IAT process for municipal wastewater treatment]. 1940 86

Aminomethylphosphonic acid (AMPA) is formed in glyphosate-treated glyphosate-resistant (GR) and glyphosate-sensitive (GS) soybean [Glycine max (L.) Merr.] plants and is known to cause yellowing in soybean. Although, AMPA is less phytotoxic than glyphosate, its mode of action is different from that of glyphosate and is still unknown. Greenhouse studies were conducted at Stoneville, MS to determine the effects of AMPA on plant growth, chlorophyll content, photosynthesis, nodulation, nitrogenase activity, nitrate reductase activity, and shoot nitrogen content in GR and GS soybeans. AMPA was applied to one- to two-trifoliolate leaf stage soybeans at 0.1 and 1.0 kg ha(-1), representing a scenario of 10% and 100% degradation of glyphosate (1.0 kg ae ha(-1) use rate) to AMPA, respectively. Overall, AMPA effects were more pronounced at 1.0 kg ha(-1) than at 0.1 kg ha(-1) rate. Visual plant injury (18-27%) was observed on young leaves within 3d after treatment (DAT) with AMPA at the higher rate regardless of soybean type. AMPA injury peaked to 46-49% at 14 DAT and decreased to 17-18% by 28 DAT, in both soybean types. AMPA reduced the chlorophyll content by 37%, 48%, 66%, and 23% in GR soybean, and 17%, 48%, 57%, and 22% in GS soybean at 3, 7, 14, and 28 DAT, respectively. AMPA reduced the photosynthesis rate by 65%, 85%, and 77% in GR soybean and 59%, 88%, and 69% in GS soybean at 3, 7, and 14 DAT, respectively, compared to non-treated plants. Similarly, AMPA reduced stomatal conductance to water vapor and transpiration rates at 3, 7, and 14 DAT compared to non-treated plants in both soybean types. Photosynthesis rate, stomatal conductance, and transpiration rate recovered to the levels of non-treated plants by 28 DAT. Plant height and shoot dry weight at 28 DAT; nodulation, nitrogenase activity at 10 DAT, and nitrate reductase activity at 3 and 14 DAT were unaffected by AMPA. AMPA reduced root respiration and shoot nitrogen content at 10 DAT. These results suggest that a foliar application of AMPA could indirectly reduce photosynthesis through decreased chlorophyll content in GR and GS soybean up to 14 DAT, but affected plants can recover to normal growth by 28 DAT.
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PMID:Physiological responses of glyphosate-resistant and glyphosate-sensitive soybean to aminomethylphosphonic acid, a metabolite of glyphosate. 2119 Jul 14


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