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)

4-(4-Chlorophenyl)piperidine analogues each bearing a thioacetamide side chain appendage similar to that found in the wake-promoting drug modafinil have been synthesized. The transporter inhibitory activity of both the cis and trans isomers of these 3,4-disubstituted piperidines in both their (+)- and (-)-enantiomeric forms was determined. These studies reveal that the (-)-cis analogues exhibit dopamine transporter/norepinephrine transporter (DAT/NET) selectivity as was previously reported for the (+)-trans analogues. On the other hand, the (-)-trans and the (+)-cis isomers show serotonin transporter (SERT) or SERT/NET selectivity. Among them, (+)-cis-5b shows a low nanomolar Ki for the NET with 39-fold and 321-fold lower potency at the DAT and SERT, respectively, thus making it a useful pharmacological research tool for exploring NET-associated behavioral signatures. On the other hand, several of the compounds described herein, such as (+)-trans-5c, show comparable activity at all three transporters. Because broad-spectrum transporter inhibitors have been hypothesized to exhibit a more rapid onset of action and/or a greater efficacy as antidepressant agents than those selective for SERT or SERT + NET, some of the present compounds will be valuable to study in animal models of depression.
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PMID:Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors. 1633 21

Although the mechanisms of cocaine reward have been well characterized, the pharmacological basis of cocaine's aversive effects is less understood. Using the conditioned taste aversion (CTA) preparation, the present study examined the role of monoamine uptake inhibition in cocaine's aversive effects by comparing cocaine to three reuptake inhibitors with relative specificity for the transporters of dopamine (DAT; GBR 12909), norepinephrine (NET; desipramine) and serotonin (SERT; clomipramine). Specifically, 104 male Sprague-Dawley rats were given 20-min access to a novel saccharin solution followed immediately by a subcutaneous injection of cocaine, GBR 12909, desipramine, clomipramine (each at 18, 32 or 50 mg/kg; 12 groups) or drug vehicle (equivolume to the highest cocaine dose). Over trials, cocaine and desipramine each dose-dependently suppressed saccharin consumption and did so in an equivalent manner when matched by dose. However, both GBR 12909 and clomipramine conditioned weaker aversions than cocaine at the two lowest doses (18 and 32 mg/kg). At the highest dose (50 mg/kg), GBR 12909 produced equivalent suppression of saccharin consumption to cocaine while clomipramine's conditioned suppression remained relatively weak at this dose. These results suggest that cocaine's adrenergic actions resulting from NET inhibition may play a more significant role in the mediation of its aversive effects than its actions at DAT and SERT.
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PMID:Assessment of monoamine transporter inhibition in the mediation of cocaine-induced conditioned taste aversion. 1633 62

Synaptic neurotransmission in the central nervous system (CNS) requires the precise control of the duration and the magnitude of neurotransmitter action at specific molecular targets. At the molecular level, neurotransmitter signaling is dynamically regulated by a diverse set of macromolecules including biosynthetic enzymes, secretory proteins, ion channels, pre- and postsynaptic receptors and transporters. Monoamines, 5-hydroxytryptamine or serotonin (5-HT), norepinephrine (NE), and dopamine (DA) play an important modulatory role in the CNS and are involved in numerous physiological functions and pathological conditions. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine. Monoamine transporters are the sites of action for widely used antidepressants and are high affinity molecular targets for drugs of abuse including cocaine, amphetamine, and 3,4-methylenedioxymetamphetamine (MDMA) "Ecstasy." Monoamine transporters also serve as molecular gateways for neurotoxins. Emerging evidence indicates that regulation of transporter function and surface expression can be rapidly modulated by "intrinsic" transporter activity itself, and antidepressant and psychostimulant drugs that block monoamine transport have a profound effect on transporter regulation. Therefore, disregulations in the functioning of monoamine transporters may underlie many disorders of transmitter imbalance such as depression, attention deficit hyperactivity disorder, and schizophrenia. This review integrates recent progress in understanding the molecular mechanisms of monoamine transporter regulation, in particular, posttranscriptional regulation by phosphorylation and trafficking linked to cellular protein kinases, protein phosphatases, and transporter interacting proteins. The review also discusses the possible role of psychostimulants and antidepressants in influencing monoamine transport regulation.
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PMID:Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. 1635 49

Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.
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PMID:Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. 1640 98

Dopamine, serotonin, and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research because the modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT1A, 5HT1B, 5HT1C, D1, D2, or D3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4-dichlorophenyl)- (4u) and the 1-naphthyl- (4t) 2-pyrrolidin-1-yl-pentan-1-one analogues.
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PMID:1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. 1648 Feb 78

1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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PMID:Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677. 1663 98

Cotransporters use energy stored in Na+ or H+ gradients to transport neurotransmitters or other substrates against their own gradient. Cotransport is rapid and efficient, and at synapses it helps terminate signaling. Cotransport in norepinephrine (NET), epinephrine (EpiT), dopamine (DAT), and serotonin (SERT) transporters couples downhill Na+ flux to uphill transmitter flux. NETs, for example, attenuate signaling at adrenergic synapses by efficiently clearing NE from the synaptic cleft, thus preparing the synapse for the next signal. Transport inhibition with tricyclic antidepressants prolongs neurotransmitter presence in the synaptic cleft, potentially alleviating symptoms of depression. Transport inhibition with cocaine or amphetamine, which respectively block or replace normal transport, may result in hyperactivity. Little is known about the kinetic interactions of substrates or drugs with transporters, largely because the techniques that have been successful in discovering trans- porter agonists and antagonists do not yield detailed kinetic information. Mechanistic data are for the most part restricted to global parameters, such as Km and Vmax, measured from large populations of transporter molecules averaged over thousands of cells. Three relatively new techniques used in transporter research are electrophysiology, amperometry, and microfluorometry. This review focuses on fluorescence-based methodologies, which--unlike any other technique-permit the simultaneous measurement of binding and transport. Microfluorometry provides unique insights into binding kinetics and transport mechanisms from a quantitative analysis of fluorescence data. Here we demonstrate how to quantify the number of bound substrate molecules, the number of transported substrate molecules, and the kinetics of substrate binding to individual transporters. Although we describe experiments on a specific neurotransmitter transporter, these methods are applicable to other membrane proteins.
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PMID:Molecular microfluorometry: converting arbitrary fluorescence units into absolute molecular concentrations to study binding kinetics and stoichiometry in transporters. 1672 29

A series of cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties. The results show that binding to the dopamine and serotonin transporters (DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol pimelic acid ester/amide (5b) had an IC50 of 3.8 nM at the DAT. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol sebacic acid ester/amide (5e) had a Ki of 1.9 nM at the 5-HTT and was 68- and 737-fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due to their specific conformational properties.
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PMID:Synthesis and monoamine transporter binding properties of 2,3-cyclo analogues of 3beta-(4'-aminophenyl)-2beta-tropanemethanol. 1685 64

2-[(Diphenylmethyl) sulfinyl]acetamide (modafinil), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by positron emission tomography imaging; in vitro, we determined modafinil activity at the DAT, NET, SERT, and rhesus monkey trace amine receptor 1 (TA1). In rhesus monkey, modafinil occupancy of striatal DAT was detected by [(11)C]2beta-carbomethoxy-3beta-4-(fluorophenyl)tropane and of thalamic NET by [(11)C](S,S)-2-(alpha-(2-methoxyphenoxy)-benzyl)morpholine. In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor. Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12%, n = 4; 8 mg/kg: 54 +/- 3%, n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.8%, n = 6; 8 mg/kg: 44 +/- 12%; n = 2). In vitro, modafinil inhibited [(3)H]dopamine (IC(50) = 6.4 microM), [(3)H]norepinephrine (IC(50) = 35.6 microM), and [(3)H]serotonin (IC(50) > 500 microM) transport via the human DAT, NET, and SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but it augmented a monoamine transporter-dependent enhancement of phenethylamine activation of TA1 in TA1-DAT and TA1-NET cells, but not in TA1-SERT cells. The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.
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PMID:Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. 1688 32

Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very different psychostimulant effects when compared with another inhibitor, cocaine. Taking advantage of the differential sensitivity of the dopamine and the norepinephrine transporters (DAT and NET) to benztropine and bupropion, we have used site-directed mutagenesis to produce gain-of-function mutants in NET which demonstrate that Ala279 in the trans-membrane domain 5 (TM5) and Ser359 in the TM7 of DAT are responsible for the higher sensitivity of DAT to both bupropion and benztropine. Substitution of these two DAT residues into the NET background does not alter the potency of NET-selective inhibitors, such as desipramine. The results from experiments examining the ability of DAT-selective inhibitors to displace [3H]nisoxetine binding in NET gain-of-function mutants suggest that Ser359 contributes to the initial binding of the inhibitor, and that Ala279 may influence subsequent steps involved in the blockade of translocation. Thus, these studies begin to identify residues that are important for the unique molecular interactions of benztropine and bupropion with the DAT, and that ultimately may contribute to the distinct behavioral actions of these drugs.
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PMID:Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters. 1692 64


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