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 synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
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PMID:Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one. 1859 16

Drug abuse is a risk factor for neurological complications in HIV infection. Cocaine has been shown to exacerbate HIV-associated brain pathology and enhance neurotoxicity of HIV-1 Tat and gp120 proteins. In this study, we found that the selective inhibitor of dopamine transporter (DAT) function, 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-(3-phenylpropyl) piperazine (GBR 12909, vanoxerine), but not the selective inhibitors of serotonin and norepinephrine (SERT and NET) transporters, sertraline and nizoxetine, emulated cocaine-mediated enhancement of Tat neurotoxicity in rat fetal midbrain primary cell cultures. Similar to cocaine, the significant increase of Tat toxicity in midbrain cell cultures was observed at micromolar dose (5microM) of GBR 12909. However, different doses of another selective dopamine uptake inhibitor, WIN 35428 did not affect Tat neurotoxicity. The study supports the hypothesis that changes in control of dopamine (DA) homeostasis are important for the cocaine-mediated enhancement of HIV-1 Tat neurotoxicity. Our results also demonstrate that inhibitors of DA uptake, which can bind to different domains of DAT, differ in their ability to mimic synergistic toxicity of cocaine and HIV-1 Tat in the midbrain cell culture.
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PMID:Different effects of selective dopamine uptake inhibitors, GBR 12909 and WIN 35428, on HIV-1 Tat toxicity in rat fetal midbrain neurons. 1860 82

Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT+/- mice that were not hyperactive as well as in DAT-/- mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT-/- mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these effects of DAT KO in animal models of depression may be because of the confounding effects of hyperactivity, mice were also assessed in a sucrose consumption test. Sucrose consumption was increased in DAT KO mice consistent with reduced anhedonia, and inconsistent with competitive hyperactivity; no increases were observed in SERT KO or NET KO mice. In summary, the effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.
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PMID:Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions. 1869 Jan 11

Ester analogs of (+/-)3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol were synthesized and evaluated for binding at DAT, SERT, NET, and sigma1 receptors, and compared to GBR 12909 and several known sigma1 receptor ligands. Most of these compounds demonstrated high affinity (K(i)=4.3-51 nM) and selectivity for the DAT among the monoamine transporters. S- and R-1-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-2-ol were also prepared wherein modest enantioselectivity was demonstrated at the DAT. However, no enantioselectivity at sigma1 receptors was observed and most of the ester analogs of the more active S-enantiomer showed comparable binding affinities at both DAT and sigma1 receptors with a maximal 16-fold DAT/sigma1 selectivity.
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PMID:Dual DAT/sigma1 receptor ligands based on 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol. 1877 92

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

Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
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PMID:Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain. 1895 38

Biogenic amine transporters for serotonin, norepinephrine and dopamine (SERT, NET and DAT respectively), are the key players terminating transmission of these amines in the central nervous system by their high-affinity uptake. They are also major targets for many antidepressant drugs. Interestingly however, drugs targeted to a specific transporter do not appear to be as clinically efficacious as those that block two or all three of these transporters. A growing body of literature, reviewed here, supports the idea that promiscuity among these transporters (the uptake of multiple amines in addition to their "native" transmitter) may account for improved therapeutic effects of dual and triple uptake blockers. However, even these drugs do not provide effective treatment outcomes for all individuals. An emerging literature suggests that "non-traditional" transporters such as organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT) may contribute to the less than hoped for efficacy of currently prescribed uptake inhibitors. OCT and PMAT are capable of clearing biogenic amines from extracellular fluid and may serve to buffer the effects of frontline antidepressants, such as selective serotonin reuptake inhibitors. In addition, polymorphisms that occur in the genes encoding the transporters can lead to variation in transporter expression and function (e.g. the serotonin transporter linked polymorphic region; 5-HTTLPR) and can have profound effects on treatment outcome. This may be accounted for, in part, by compensatory adaptations in other transporters. This review synthesizes the existing literature, focusing on serotonin to illustrate and revive a model for the rationale design of improved antidepressants.
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PMID:Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. 1902 90

Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [Garcia, J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157-158.]. Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin.
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PMID:Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion. 1937 54

Cocaine, a potent addictive substance, is an inhibitor of monoamine transporters, including DAT (dopamine transporter), SERT (serotonin transporter) and NET (norepinephrine transporter). Cocaine administration induces complex behavioral alterations in mammals, but the underlying mechanisms are not well understood. Here, we tested the effect of cocaine on C. elegans behavior. We show for the first time that acute cocaine treatment evokes changes in C. elegans locomotor activity. Interestingly, the neurotransmitter serotonin, rather than dopamine, is required for cocaine response in C. elegans. The C. elegans SERT MOD-5 is essential for the effect of cocaine, consistent with the role of cocaine in targeting monoamine transporters. We further show that the behavioral response to cocaine is primarily mediated by the ionotropic serotonin receptor MOD-1. Thus, cocaine modulates locomotion behavior in C. elegans primarily by impinging on its serotoninergic system.
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PMID:Cocaine modulates locomotion behavior in C. elegans. 1953 76

A series of dimeric phenyl tropanes consisting of two molecules of 4-chloro, 4-iodo or 4-(3-thiopheno)-phenyl tropane tethered together at the carboxylic acid moiety by a diamine or diol linker were prepared. The diamines used were a variety of linear, cyclic and aromatic diamines, while the diol tethered compounds were prepared by 'click' chemistry and contained a triazole in the linker. The new compounds were tested for binding to hDAT, hSERT and hNET. Amide linked chlorophenyl tropanes with an aromatic linker was found to be potent and selective DAT inhibitors with the best K(i) value for hDAT being 6nM. The ester linked halophenyl tropanes were more potent but displayed little selectivity in inhibition of monoamine transporter binding. Among the studied compounds an ester linker of 10 atoms between the tropane moieties gave the highest affinity. One monomeric phenyl tropane was made for comparison and was found to be less potent than the dimeric counterparts towards SERT and NET but remain highly active against DAT. Dimeric thiophenophenyl tropanes were in general found to be comparatively poor monoamine transporter binders, but significant gains of affinity of up to 45-fold could be achieved with selected dimeric chlorophenyl tropanes compared to the parent monomer. This observation implies that a secondary binding site that has affinity for phenyl tropanes, most likely the putative S2 site, is located within 13A of the primary central S1 binding site.
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PMID:An extended study of dimeric phenyl tropanes. 1956 Sep 30


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