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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both dopamine uptake inhibitors and sigma(1) receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, sigma(1) antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a sigma(1) receptor antagonist that binds to the DAT (K(i) = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and sigma(1) receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and sigma(1) receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4'-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K(i) = 8.5 nM), was selective over serotonin transporter (SERT/DAT = 94), norepinephrine transporter (NET/DAT = 63), and sigma(1) receptor binding (sigma(1)/DAT = 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170- and 140-fold, respectively) and DAT over NET (219- and 190-fold, respectively) but were essentially equipotent at DAT and sigma(1) receptors (10; K(i) = 77 and 124 nM, respectively, 17; K(i) = 28 and 13 nM, respectively). CoMFA studies at both DAT and sigma(1) receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and sigma(1) receptors may provide a novel approach toward designing medications for cocaine abuse.
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PMID:Dual probes for the dopamine transporter and sigma1 receptors: novel piperazinyl alkyl-bis(4'-fluorophenyl)amine analogues as potential cocaine-abuse therapeutic agents. 1280 Dec 23

Recently we showed evidence that mutation of Tyr-335 to Ala (Y335A) in the human dopamine transporter (hDAT) alters the conformational equilibrium of the transport cycle. Here, by substituting, one at a time, 16 different bulky or charged intracellular residues, we identify three residues, Lys-264, Asp-345, and Asp-436, the mutation of which to alanine produces a phenotype similar to that of Y335A. Like Y335A, the mutants (K264A, D345A, and D436A) were characterized by low uptake capacity that was potentiated by Zn(2+). Moreover, the mutants displayed lower affinity for cocaine and other inhibitors, suggesting a role for these residues in maintaining the structural integrity of the inhibitor binding crevice. The conformational state of K264A, Y335A, and D345A was investigated by assessing the accessibility to MTSET ([2-(trimethylammonium)ethyl]-methanethiosulfonate) of a cysteine engineered into position 159 (I159C) in transmembrane segment 3 of the MTSET-insensitive "E2C" background (C90A/C306A). Unlike its effect at the corresponding position in the homologous norepinephrine transporter (NET I155C), MTSET did not inhibit uptake mediated by E2C I159C. Furthermore, no inhibition was observed upon treatment with MTSET in the presence of dopamine, cocaine, or Zn(2+). Without Zn(2+), E2C I159C/K264A, E2C I159C/Y335A, and E2C I159C/D345A were also not inactivated by MTSET. In the presence of Zn(2+) (10 microm), however, MTSET (0.5 mm) caused up to approximately 60% inactivation. As in NET I155C, this inactivation was protected by dopamine and enhanced by cocaine. These data are consistent with a Zn(2+)-dependent partial reversal of a constitutively altered conformational equilibrium in the mutant transporters. They also suggest that the conformational equilibrium produced by the mutations resembles that of the NET more than that of the DAT. Moreover, the data provide evidence that the cocaine-bound state of both DAT mutants and of the NET is structurally distinct from the cocaine-bound state of the DAT.
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PMID:Identification of intracellular residues in the dopamine transporter critical for regulation of transporter conformation and cocaine binding. 1459 28

The biogenic amine transporters belong to the class of Na+/Cl--coupled solute carriers and include the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT). These transporters are the primary targets for the action of many psychoactive compounds including the most commonly used antidepressants as well as widely abused drugs such as cocaine and amphetamines. In spite of their pharmacological importance, still little is known about their higher structural organization and the molecular mechanisms underlying the substrate translocation process. In this review, it will be described how we have used Zn2+-binding sites as a tool to probe the structure and function of Na+/Cl--coupled biogenic amine transporters with specific focus on the human DAT (hDAT). The work has not only led to the definition of the first structural constrains in the tertiary structure of this class of transporters, but also allowed inferences about conformational changes accompanying substrate translocation and residues critical for regulating the equilibrium between different functional states in the transport cycle.
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PMID:Probing dopamine transporter structure and function by Zn2+-site engineering. 1461 49

In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT(1A) and 5-HT(2A) receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT(1A) and 5-HT(2A) receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and alpha(2) receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K(i) < 25 nM and a NET/SERT ratio <10. Compound (-)-15j (coded as F-98214-TA for development studies) showed a dual binding profile with very high affinity values for SERT and NET (K(i) = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.
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PMID:Syntheses and binding studies of new [(aryl)(aryloxy)methyl]piperidine derivatives and related compounds as potential antidepressant drugs with high affinity for serotonin (5-HT) and norepinephrine (NE) transporters. 1464 May 59

Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.
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PMID:Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. 1465 7

Several 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes (3a-t) were evaluated for their ability to inhibit radioligand binding at the DAT, 5-HTT, and NET as well as in gross observation and locomotor activity in mice and in rats trained to discriminate cocaine. All compounds showed high affinity for the DAT. The IC(50) values ranged from 0.5 to 26 nM. With the exception of 3e and 3f, which have no substituent on the 2beta-(1,2-isoxazole) ring, all compounds were selective for the DAT relative to the 5-HTT and NET. No compound showed death when dosed at 100 mg/kg; however, most compounds did show signs typical of dopamine activity. The ED(50) values for 2beta-(1,2-isoxazoles) that caused locomotor stimulation ranged from 0.2 to 12.8 mg/kg. Most compounds showed slower on-set and longer duration of action relative to cocaine. Surprisingly, 3beta-(4-methylphenyl)-2beta-[3-(4'-chlorophenyl)isoxazol-5-yl]tropane (3p) and 3beta-(4-methylphenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (3r) did not produce significant increases in locomotor activity. In the cocaine discrimination test, all analogues showed full or at least 50% generalization with the exception of 3p, which did not show generalization. Importantly, both the locomotor activity and the cocaine discrimination ED(50)values were correlated with the DAT binding but not 5-HTT and NET binding. This provides further support for the dopamine hypothesis of cocaine abuse. High DAT affinity and selectivity, increased locomotor activity with slow onset and long duration of action, and generalization to cocaine shown by the 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes are properties thought necessary for a pharmacotherapy for treating cocaine abuse.
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PMID:Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes. 1471 3

2beta-Carbomethoxy-3beta-[4'-((Z)-2-iodoethenyl)phenyl]tropane (ZIET) and 2beta-carbomethoxy-3beta-[4'-((Z)-2-bromoethenyl)phenyl]tropane (ZBrET) were synthesized as well as their nortropane congeners ZIENT and ZBrENT. Binding affinities of these compounds were determined in cells transfected to express human SERT, DAT, and NET using [3H]citalopram, [125I]RTI-55, and [3H]nisoxetine, respectively. Both ZIET and ZBrET displayed high affinity for the SERT (Ki = 0.11 and 0.08 nM, respectively). The affinities of ZIET and ZBrET for the DAT were 200 and 38-fold lower, respectively, than for the SERT. [11C]ZIET and [11C]ZBrET were prepared by alkylation of their corresponding nortropanes with [11C]methyl iodide in approximately 30% radiochemical yield (decay-corrected to end of bombardment, EOB). High specific activity [123I]ZIET was synthesized in 33% radiochemical yield (decay-corrected) by treating the 2beta-carbomethoxy-3beta-[4'-((Z)-2-trimethylstannylethenyl)phenyl]tropane (3) with no carrier-added sodium [123I]iodide and hydrogen peroxide in ethanolic HCl. Biodistribution studies in rats indicated that [123I]ZIET enters the brain readily and accumulates in SERT-rich regions. Blocking studies performed in rats demonstrated that [123I]ZIET was selective and specific for SERT-rich regions (e.g. thalamus, brainstem, and striatum). MicroPET brain imaging studies in monkeys demonstrated that [11C]ZIET and [11C]ZBrET uptakes were selectivity localized in the putamen, midbrain, caudate, thalamus, pons, and medulla. Radioactivity in the regions of high SERT density of monkey brain was displaceable with citalopram except in the putamen and caudate. Radioactivity uptake in these DAT-rich regions was significantly displaceable either by preadministration of citalopram followed by injection of RTI-113 (or vice-versa) or by administration of a mixture of DAT and SERT ligands. In conclusion, the high yield, high specific activity, one-step radiolabeling method, high selectivity and favorable kinetics, and the good results obtained with [123I]ZIET in rats support the candidacy of [11C]ZIET for in vivo visualization and quantification of brain SERT.
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PMID:Synthesis, radiosynthesis, and biological evaluation of carbon-11 and iodine-123 labeled 2beta-carbomethoxy-3beta-[4'-((Z)-2-haloethenyl)phenyl]tropanes: candidate radioligands for in vivo imaging of the serotonin transporter. 1497 92

A series of racemic 6-hydroxy and carboalkoxy substituted-4('),4"-difluorobenztropines was synthesized and evaluated for binding at the dopamine (DAT), the serotonin (SERT), the norepinephrine (NET) transporters, and the muscarinic M1 receptor. Each of the analogues displaced [(3)H]WIN 35,428 (DAT) with a range of affinities from 5.81 to 175 nM and [(3)H]pirenzepine (M1), with a range of affinities ( K(i)= -8430 nM). Binding affinities at the SERT and the NET were generally low.
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PMID:The effect of 6-substituted-4',4"-difluorobenztropines on monoamine transporters and the muscarinic M1 receptor. 1514 93

A qualitative model for the binding pocket proximal to the 3alpha-substituent of the piperidine-based monoamine transporter ligands was proposed and tested. Based on this model, a new series of druglike 3alpha-modified piperidine-based analogues of cocaine were designed, synthesized, and studied for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. We found that the insertion of at least one additional methylene group between the piperidine ring and the polar group in the 3alpha-substituent dramatically improves the activity of the compounds that are generally inactive without this additional linker. Molecular modeling analysis showed that the more flexible 3alpha-substituents can avoid unfavorable interactions with the binding sites of DAT, SERT, and NET. The present results may have important implications for the elucidation of the structural differences between DA, 5-HT, and NE transporters and for the further design of new leads for development of cocaine abuse medication as well as certain neurological disorders such as ADHD and depression.
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PMID:Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring. 1516 83

A new serotonin transporter (SERT) ligand, [11C]2-[2-(dimethylaminomethylphenylthio)]-5-fluorophenylamine (10, [11C]AFA), was synthesized and evaluated as a candidate PET radioligand in pharmacological and pharmacokinetic studies. As a PET radioligand, AFA (8) can be labeled with either C-11 or F-18. In vitro, AFA displayed high affinity for SERT (Ki 1.46 +/- 0.15 nM) and lower affinity for norepinephrine transporter (NET, Ki 141.7 +/- 47.4 nM) or dopamine transporter (DAT, Ki > 10,000 nM). [11C]AFA (10) was prepared from its monomethylamino precursor 9 by reaction with high specific activity [11C]methyl iodide. Radiochemical yield was 43 +/- 20% based on [11C]methyl iodide at end of bombardment (EOB, n = 10) and specific activity was 2,129 +/- 1,369 Ci/mmol at end of synthesis (EOS, n = 10). Biodistribution studies in rats indicated that [11C]AFA accumulated in brain regions known to contain high concentrations of SERT. Binding in SERT-rich brain regions was reduced significantly by pretreatment with either the cold compound 8 or with the selective serotonin reuptake inhibitor (SSRI) citalopram, but not by the selective norepinephrine reuptake inhibitor nisoxetine, thus underlining its in vivo binding selectivity and specificity for SERT. Imaging experiments in baboons demonstrated that the uptake pattern of [11C]AFA in the baboon brain is consistent with the known distribution of SERT, with highest activity levels in the midbrain and thalamus, followed by striatum, hippocampus, and cortical regions. Activity levels in the baboon brain peaked at 15-40 min after radioligand injection, indicating a fast uptake kinetics for [11C]AFA. Pretreatment of the baboon with citalopram (4 mg/kg) significantly reduced the specific binding of [11C]AFA in all SERT-containing brain regions. Kinetic analysis revealed that the regional equilibrium specific to non-specific partition coefficients (V3") of [11C]AFA are similar to those of [11C]McN5652, but lower than those of [11C]AFM or [11C]DASB. In summary, [11C]AFA appears to be an appropriate PET radioligand with a fast brain uptake kinetics:
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PMID:A PET imaging agent with fast kinetics: synthesis and in vivo evaluation of the serotonin transporter ligand [11C]2-[2-dimethylaminomethylphenylthio)]-5-fluorophenylamine ([11C]AFA). 1524 63


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