Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:032070 (DAT)
 1,465 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to determine the selectivity of (S,S)-2-(alpha-(2-methoxyphenoxy)benzyl)morpholine (MeNER) binding to norepinephrine transporters (NET). Quantitative autoradiography studies of NET binding were performed in brains of wildtype mice and those of mutant mice lacking one or two alleles of the NET gene. [3H]MeNER binding in the wildtype mouse brains was consistent with previously reported distributions of NET. Highest levels were found in the locus coeruleus, thalamus, hypothalamus, and bed nucleus of stria terminalis. Specific binding in these regions was approximately 50% in the heterozygous NET mice and negligible in the NET knockout mice. Binding in the wildtype mouse brains was displaced by the NET ligand, nisoxetine, but not by the serotonin or dopamine transporter blockers, citalopram or GBR 12935. [3H]MeNER displayed much higher affinity for NET than for SERT or DAT in homogenate binding studies. Each of these features supports the binding specificity of this candidate in vivo NET ligand.
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PMID:Specific in vitro binding of (S,S)-[3H]MeNER to norepinephrine transporters. 1572 40

A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at mu-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (K(i) = 0.0072 muM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and mu-opioid receptors (mu/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K(i) = 0.125 muM) and was the most selective ligand for the DAT over mu-opioid receptors (mu/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the mu-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.
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PMID:Synthesis and biological evaluation of meperidine analogues at monoamine transporters. 1574 77

We used a knock-in strategy to generate two lines of mice expressing Cre recombinase under the transcriptional control of the dopamine transporter promoter (DAT-cre mice) or the serotonin transporter promoter (SERT-cre mice). In DAT-cre mice, immunocytochemical staining of adult brains for the dopamine-synthetic enzyme tyrosine hydroxylase and for Cre recombinase revealed that virtually all dopaminergic neurons in the ventral midbrain expressed Cre. Crossing DAT-cre mice with ROSA26-stop-lacZ or ROSA26-stop-YFP reporter mice revealed a near perfect correlation between staining for tyrosine hydroxylase and beta-galactosidase or YFP. YFP-labeled fluorescent dopaminergic neurons could be readily identified in live slices. Crossing SERT-cre mice with the ROSA26-stop-lacZ or ROSA26-stop-YFP reporter mice similarly revealed a near perfect correlation between staining for serotonin-synthetic enzyme tryptophan hydroxylase and beta-galactosidase or YFP. Additional Cre expression in the thalamus and cortex was observed, reflecting the known pattern of transient SERT expression during early postnatal development. These findings suggest a general strategy of using neurotransmitter transporter promoters to drive selective Cre expression and thus control mutations in specific neurotransmitter systems. Crossed with fluorescent-gene reporters, this strategy tags neurons by neurotransmitter status, providing new tools for electrophysiology and imaging.
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PMID:Targeted gene expression in dopamine and serotonin neurons of the mouse brain. 1576 33

Previous studies identified partial inhibitors of serotonin (5-HT) transporter and dopamine transporter binding. We report here on a partial inhibitor of 5-HT transporter (SERT) binding identified among a group of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine analogs (4-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-1-(2-trifluoromethyl-benzyl)-piperidine; TB-1-099). Membranes were prepared from rat brains or human embryonic kidney cells expressing the cloned human dopamine (hDAT), serotonin (hSERT), and norepinephrine (hNET) transporters. beta-(4'-(125)Iodophenyl)tropan-2beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding and other assays followed published procedures. Using rat brain membranes, TB-1-099 weakly inhibited DAT binding (K(i) = 439 nM), was inactive at NET binding ([(3)H]nisoxetine), and partially inhibited SERT binding with an extrapolated plateau ("A" value) of 20%. Similarly, TB-1-099 partially inhibited [(125)I]RTI-55 binding to hSERT with an extrapolated plateau (A value) of 14%. Upon examining the effect of increasing concentrations of TB-1-099 on the apparent K(d) and B(max) of [(125)I]RTI-55 binding to hSERT, we found that TB-1-099 decreased the B(max) in a dose-dependent manner and affected the apparent K(d) in a manner well described by a sigmoid dose-response curve. TB-1-099 increased the K(d) but not to the magnitude expected for a competitive inhibitor. In rat brain synaptosomes, TB-1-099 noncompetitively inhibited [(3)H]5-HT, but not [(3)H]dopamine, uptake. Dissociation experiments indicated that TB-1-099 promoted the rapid dissociation of a small component of [(125)I]RTI-55 binding to hSERT. Association experiments demonstrated that TB-1-099 slowed [(125)I]RTI-55 binding to hSERT in a manner unlike that of the competitive inhibitor indatraline. Viewed collectively, these results support the hypothesis that TB-1-099 allosterically modulates hSERT binding and function.
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PMID:Studies of the biogenic amine transporters. XI. Identification of a 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) analog that allosterically modulates the serotonin transporter. 1586 May 77

ADHD (attention hyperactivity disorder) is a polygenetic disorder with various candidate genes. At this time, more than thirty dopaminergic, noradrenergic, serotonergic and GABA-ergic genes are known. The research of only some candidate genes (DRD4, DAT, DRD5, DBH, 5HTT, HTR1B and SNAP25) brought relatively consistent results confirming the heredity of ADHD syndromes. The results of research of other genes (DRD2, DRD3, MAO, ADR2A, GABA A3, GABA B3) are not clear yet. This paper summarizes the most important genetic data in correlations with biochemical periphery parameters (especially for DBH, HVA, MHPG, serotonin). Hypothetically, certain subgroups of ADHD may be identified by correlation of biochemical characteristics and some candidate genes. The paper discusses some implications for future research. Review.
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PMID:Biochemical markers and genetic research of ADHD. 1613 97

Serotonin and dopamine transporter (SERT, DAT) availabilities have prospectively been investigated using [123I]beta-CIT and single photon emission computed tomography in subjects with obsessive-compulsive disorder under treatment with the selective serotonin reuptake inhibitor citalopram. SERT availability decreased by a mean 36.5%, whereas DAT availability increased by about 40%. The data point at a citalopram induced modulation of both serotonergic and dopaminergic activity and support the notion of functional interactions of monoaminergic systems in the human brain.
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PMID:SERT and DAT availabilities under citalopram treatment in obsessive-compulsive disorder (OCD). 1613 70

Membrane and vesicular monoaminergic transporters, responsible for the homeostasis of neurotransmitter pools at nerve endings, are very involved in the physiology and diseases of central nervous system. Recent progresses of cerebral molecular imaging using SPECT and PET methods allow the extend of in vivo exploration of these transporters. For this aim, an increasing number of radiopharmaceuticals labelled with [123I], [99mTc], [11C] or [18F] have been developed such as cocaine derivatives for the DAT, compounds from the diphenyl sulfide family for the SERT, and dihydrotetrabenazine derivatives for the VMAT2. These functional imaging methods can be very useful in several neurological and psychiatric disorders which involve the monoaminergic neurotransmission systems such as Parkinson's disease, ADHD, depression and autism. For example, the DAT is a specific index of the density of dopaminergic endings which progressively degenerate in Parkinson's disease. In vivo exploration of this transporter can therefore be a relevant way (i) to realize an early detection of the loss of dopaminergic neurons, (ii) to assess the progression of the disease, (iii) to validate and improve the efficacy of new therapeutic strategies such as neuroprotection and neuroreparation. In all, the extend of in vivo exploration of monoamine transporters will allow great progress for (1) knowledge of physiopathological mechanisms of brain disorders, (2) early diagnosis of cerebral dysfunctions, allowing early use of new therapies, (3) selection of homogenous classes of subjects for therapeutic assays, (4) objectiveness of drug-molecular target interaction, (5) follow-up of disease evolution and treatment.
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PMID:PET and SPECT exploration of central monoaminergic transporters for the development of new drugs and treatments in brain disorders. 1625 Aug 52

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

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


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