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)

The initially surprising observation that cocaine retains its rewarding effects in dopamine transporter (DAT) knockout (KO) mice led our laboratory to examine the effects of deletion of other monoaminergic genes on cocaine reward. Our initial approach to this problem was to combine DAT KO mice with serotonin transporter (SERT) KO mice to make combined DAT/SERT KO mice. The combination of these knockouts eliminates cocaine reward as assessed in the conditioned place preference (CPP) paradigm. We have also identified evidence that, in the absence of DAT, there is greater participation in cocaine reward by serotonin (SERT) and norepinephrine (NET) transporters. Both NET and SERT blockers (nisoxetine and fluoxetine) produced significant CPPs in DAT KO mice, but not in wild-type (WT) mice. The striking elimination of cocaine CPP in combined DAT/SERT KO mice contrasts with effects that we have identified in combined NET/SERT knockout mice, which display increases in cocaine reward, and with recent reports that suggest that DAT/NET combined KOs retain substantial cocaine CPP. Overall, these studies indicate important requirements for several monoaminergic system genes to fully explain cocaine reward, in particular those expressed by dopamine and serotonin systems.
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PMID:Molecular mechanisms underlying the rewarding effects of cocaine. 1554 99

Preparation of cocaine analogues has been aimed largely at development of stable compounds with high affinity and selectivity for the dopamine transporter (DAT). We now report the synthesis and monoamine transporter affinity of 10 new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes. Among these, compound 4b exhibited very high affinity for the serotonin transporter (SERT: K(i)=17 pM) and good selectivity over dopamine (DAT: 710-fold) and norepinephrine transporters (NET: 11,100-fold).
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PMID:Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency. 1568 27

The structural requirements for high affinity at the serotonin transporter (5-HTT) have been investigated through the preparation of rigid paroxetine analogs. Tropane-derived analogs (4a-i) of paroxetine (2) were designed and synthesized as potential inhibitors of serotonin reuptake based on the structural and biological similarity between the two compound classes. Overall, the affinity of tropane-derived analogs at the 5-HTT was found to be at least an order of magnitude lower than that of paroxetine and ranged from 2-400nM. The reduced affinity at the 5-HTT may be attributed to the inability of the rigid tropane-derived analogs to adopt conformations favored by the 5-HTT. Within the series of tropane analogs, the 2beta,3beta- and 2beta,3alpha-isomers, 4a and 4d, were the most potent at the DAT and NET and are also significantly more potent than paroxetine (2) suggesting that their reduced conformational flexibility maximizes residence time in conformations favored by these transporters. Examination of the previously published preparation and structural assignment of 4a by additional NMR and X-ray crystallographic data has established that nucleophilic addition to the intermediate 2beta-methanesulfonyloxymethyl-3beta-(4-fluorophenyl)tropane unexpectedly provided the aza-bicyclo[3.2.2]nonane derivative 10a.
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PMID:Synthesis, structural identification, and ligand binding of tropane ring analogs of paroxetine and an unexpected aza-bicyclo[3.2.2]nonane rearrangement product. 1575 46

The norepinephrine (NE) transporter (NET) mediates the removal of NE from synaptic spaces and is a major target for antidepressants, amphetamine and cocaine. Previously, we have shown that syntaxin 1A (SYN 1A) supports human NET (hNET) cell surface expression, that hNET/SYN 1A interactions are direct and mediated by the hNET N-terminus, and that the hNET/SYN 1A association limits substrate-induced hNET-associated currents [Sung, U., Apparsundaram, S., Galli, A., Kahlig, K.M., Savchenko, V., Schroeter, S., Quick, M.W., Blakely, R.D., 2003. A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity. J. Neurosci. 23, 1697-1709]. These data raise the possibility that the hNET N-terminus, and potentially its interaction with SYN 1A, might regulate other hNET conductance states, including the hNET-mediated leak current. Importantly for monoamine transporters, the leak conductance has been shown to play a critical role in regulating cell membrane potential and possibly neuronal excitability [Quick, M.W., 2003. Regulating the conducting states of a mammalian serotonin transporter. Neuron 40, 537-549]. Here we demonstrate that deletion of the binding domain for SYN 1A in the NET N-terminus robustly enhances the NET-mediated leak current as well as its selectivity for Cl- permeation under particular intracellular ionic compositions. In addition, we show that the NET N-terminus coordinates the ability of intracellular Na+ and Cl- to regulate the leak conductance. These data suggest that the NET N-terminus regulates and defines the ionic specificity of the NET-mediated leak current.
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PMID:The N-terminus of the norepinephrine transporter regulates the magnitude and selectivity of the transporter-associated leak current. 1628 33

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

Pharmacogenomics seeks to explain the variability in drug response. Neurotransmitter transporters from the SLCA6 family are direct or indirect targets for psychotropic drugs, and their genetic variations may directly influence response to antidepressant or antipsychotic drugs. Furthermore, drug transporters located in natural barriers, such as the blood brain barrier, may influence response to psychoactive substrates. In the 5'-upstream regulatory region of the neuronal serotonin transporter lays a 44-base pair insertion/deletion polymorphism resulting in a long and a short variant. Several studies have reported a better response to selective serotonin reuptake inhibitors in individuals carrying two long alleles, however, some studies report contradictory results. Moreover, several genetic variants are known in the human norepinephrine transporter gene, and though one study reports differences in antidepressant response due to the NET G1287A polymorphism, results should be replicated by others before conclusions can be drawn. Dopamine transporters play an important role in psychotropic drug response, and a variable number of tandem repeats polymorphism in the 3'-untranslated region of the dopamine transporter gene has been studied in regards to possible correlation with antipsychotic drug response but without showing an association. P-glycoprotein has been shown to influence drug concentrations in CNS but so far, the studies on genetic polymorphisms did not show effects on the phenotype of response.Thus, several studies have looked at the influence of genetic polymorphisms on psychotropic drug response gaining different results. Best evidence exists for the serotonin transporter polymorphism influencing the response to selective serotonin reuptake inhibitors but the effects are relatively small. So far, transporter genotypes are not yet eligible for individual prediction of drug response.
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PMID:Contribution of allelic variations in transporters to the phenotype of drug response. 1678 67

Even today, pharmacotherapy for mood disorders is based almost entirely on the observation in the 1950s and 1960s that agents that enhance monoamine transmitter activity are effective antidepressants. Preclinical studies have shown that long-term administration of nearly all effective antidepressants increases the efficiency of postsynaptic serotonin transmission; many also modify central noradrenergic activity. For the majority of antidepressants, these changes are the result of their ability to block serotonin and/or norepinephrine activity at their "presynaptic uptake sites" (i.e., at the serotonin transporter [SERT] or the norepinephrine transporter [NET]). Drugs that are highly selective for one transporter over another have been demonstrated to be effective and tolerable, whereas agents that act on multiple transporters may not necessarily achieve better efficacy and may result in additional adverse events. The rationale for the use of drugs that affect multiple transports is based on the suggestion that antidepressants that block both the SERT and the NET may provide better efficacy. This can only be determined through empirical studies.
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PMID:Serotonin and norepinephrine transporter binding profile of SSRIs. 1698 91

Heart failure is a cause of pulmonary vasoconstriction and remodelling, leading to pulmonary hypertension (PH) and decreased survival. The pathobiology of PH in heart failure remains incompletely understood. We investigated pulmonary vascular function and signalling molecules in early stage PH secondary to experimental heart failure. Eight beagle dogs with overpacing-induced heart failure underwent haemodynamic assessment and postmortem pulmonary arterial reactivity, morphometry and quantification of genes encoding for factors involved in vascular reactivity and remodelling: endothelin-1 (ET-1), ETA and ETB receptors, vascular endothelial growth factor (VEGF), VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), endothelial nitric oxide synthase, angiopoietin-1, bone morphogenetic protein receptors (BMPR1A and BMPR2), serotonin transporter (5-HTT) and the 5-HT(2B) receptor. Overpacing was associated with a decrease in cardiac output and an increase in pulmonary vascular pressures. However, there were no changes in pulmonary vascular resistance or in arteriolar medial thickness. There were increased expressions of genes encoding for ET-1, ETB, VEGF and VEGFR2, while expression of the other genes analysed remained unchanged. In vitro, pulmonary arteries showed decreased relaxation and increased reactivity, while systemic mammary arteries were unaffected. Early PH in heart failure is characterized by altered vasoreactivity and increased ET-1/ETB and VEGF/VEGFR2 signalling.
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PMID:Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. 1799 9

The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT(1A) receptors has been implicated in the "time lag" observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), DAT, NET, alpha (2)-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.
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PMID:Recent developments in the design of anti-depressive therapies: targeting the serotonin transporter. 1867 23

The serotonin transporter gene (SLC6A4; synonyms, SERT, 5-HTT) is expressed much more broadly during development than in adulthood. To obtain a full picture of all sites of SERT expression during development we used a new mouse model where Cre recombinase was inserted into the gene encoding the serotonin transporter. Two reporter mouse lines, ROSA26R and the Tau(mGFP), allowed to map all the cells that express SERT at any point during development. Combined LacZ histochemistry and GFP immunolabelling showed neuronal cell bodies and axon fiber tracts. Earliest recombination in embryos was visible in the periphery in the heart and liver by E10.5 followed by recombination in the brain in raphe serotonergic neurons by E12.5. Further, recombination in non-serotonin neurons was visible in the choroid plexus, roof plate, and neural crest derivatives; by E15.5, recombination was found in the dorsal thalamus, cingulate cortex, CA3 field of the hippocampus, retinal ganglion cells, superior olivary nucleus and cochlear nucleus. Postnatally, SERT mediated recombination was visible in the medial prefrontal cortex and layer VI neurons in the isocortex. Recombined cells were co-labelled with Neu-N, but not with GAD67, and were characterized by long range projections (corpus callosum, fornix, thalamocortical). This fate map of serotonin transporter expressing cells emphasizes the broad expression of SERT in non-serotonin neurons during development and clarifies the localization of SERT expression in the hippocampus and limbic cortex. The identification of targets of SSRIs and serotonin releasers during embryonic and early postnatal life helps understanding the very diverse physiological consequences of administration of these drugs during development.
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PMID:Serotonin transporter transgenic (SERTcre) mouse line reveals developmental targets of serotonin specific reuptake inhibitors (SSRIs). 1878 54


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