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1.
ACS Chem Neurosci ; 6(9): 1591-9, 2015 Sep 16.
Article in English | MEDLINE | ID: mdl-26154082

ABSTRACT

Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [(3)H]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure-activity relationship (SAR) study led to the identification of hGAT3-selective inhibitors (i.e., compounds 20 and 34) that were superior to the reference hGAT3 inhibitor, (S)-SNAP-5114, in terms of potency (low micromolar IC50 values) and selectivity (>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further pharmacological characterization of compound 20 (5-(thiophen-2-yl)indoline-2,3-dione) revealed a noncompetitive mode of inhibition at hGAT3. This suggests that this compound class, which has no structural resemblance to GABA, has a binding site different from the substrate, GABA. This was supported by a molecular modeling study that suggested a unique binding site that matched the observed selectivity, inhibition kinetics, and SAR of the compound series. These compounds are the most potent GAT3 inhibitors reported to date that provide selectivity for GAT3 over other GABA transporter subtypes.


Subject(s)
GABA Plasma Membrane Transport Proteins/metabolism , GABA Uptake Inhibitors/pharmacology , Animals , Anisoles/chemistry , Anisoles/pharmacology , Binding Sites , CHO Cells , Cricetulus , GABA Plasma Membrane Transport Proteins/genetics , GABA Uptake Inhibitors/chemical synthesis , GABA Uptake Inhibitors/chemistry , Humans , Isatin/analogs & derivatives , Kinetics , Molecular Dynamics Simulation , Molecular Structure , Nipecotic Acids/chemistry , Nipecotic Acids/pharmacology , Structure-Activity Relationship , Transfection , Tritium , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/metabolism
2.
Bioorg Med Chem ; 23(10): 2480-8, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25882526

ABSTRACT

A series of ß-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1.


Subject(s)
Amino Acids/chemistry , Carrier Proteins/antagonists & inhibitors , GABA Plasma Membrane Transport Proteins/chemistry , GABA Uptake Inhibitors/chemistry , Amino Acids/chemical synthesis , Animals , Carrier Proteins/chemistry , GABA Agonists/chemistry , GABA Uptake Inhibitors/chemical synthesis , HEK293 Cells , Humans , Ligands , Mice , Molecular Docking Simulation , Molecular Structure , Nipecotic Acids/chemistry , Protein Isoforms/chemistry , Structure-Activity Relationship , Tiagabine
3.
J Med Chem ; 58(5): 2149-58, 2015 Mar 12.
Article in English | MEDLINE | ID: mdl-25679268

ABSTRACT

Elevating GABA levels in the synaptic cleft by inhibiting its reuptake carrier GAT1 is an established approach for the treatment of CNS disorders like epilepsy. With the increasing availability of crystal structures of transmembrane transporters, structure-based approaches to elucidate the molecular basis of ligand-transporter interaction also become feasible. Experimental data guided docking of derivatives of the GAT1 inhibitor tiagabine into a protein homology model of GAT1 allowed derivation of a common binding mode for this class of inhibitors that is able to account for the distinct structure-activity relationship pattern of the data set. Translating essential binding features into a pharmacophore model followed by in silico screening of the DrugBank identified liothyronine as a drug potentially exerting a similar effect on GAT1. Experimental testing further confirmed the GAT1 inhibiting properties of this thyroid hormone.


Subject(s)
GABA Agonists/metabolism , GABA Plasma Membrane Transport Proteins/chemistry , GABA Plasma Membrane Transport Proteins/metabolism , Molecular Docking Simulation , Nipecotic Acids/metabolism , Triiodothyronine/pharmacology , gamma-Aminobutyric Acid/metabolism , Computer Simulation , GABA Agonists/chemistry , HEK293 Cells , High-Throughput Screening Assays , Humans , Models, Molecular , Molecular Structure , Nipecotic Acids/chemistry , Structure-Activity Relationship , Tiagabine , Triiodothyronine/chemistry
4.
Molecules ; 20(1): 1712-30, 2015 Jan 20.
Article in English | MEDLINE | ID: mdl-25608857

ABSTRACT

Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET.


Subject(s)
Computer Simulation , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Positron-Emission Tomography , Radiopharmaceuticals/chemical synthesis , Humans , Ligands , Norepinephrine Plasma Membrane Transport Proteins/chemistry , Radiopharmaceuticals/chemistry , Reference Standards , Sequence Alignment
5.
Bioorg Med Chem Lett ; 24(18): 4490-4495, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25127869

ABSTRACT

Since high MAO-B levels are present in early stages of AD, the MAO-B system can be designated as an appropriate and prospective tracer target of molecular imaging biomarkers for the detection of early AD. According to the preceding investigations of Mishra et al. the aim of this work was the development of a compound library of selective and reversible MAO-B inhibitors by performing bioisosteric modifications of the core structure of 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazoles. In conclusion, 13 new pyrazoline based derivatives have been prepared, which will serve as precursor substances for future radiolabeling as well as reference compounds for the investigation of increased MAO-B levels in AD.


Subject(s)
Alzheimer Disease/diagnosis , Monoamine Oxidase Inhibitors , Positron-Emission Tomography , Pyrazoles , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Dose-Response Relationship, Drug , Early Diagnosis , Humans , Molecular Structure , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Reference Standards , Structure-Activity Relationship
7.
Proc Natl Acad Sci U S A ; 110(28): 11642-7, 2013 Jul 09.
Article in English | MEDLINE | ID: mdl-23798435

ABSTRACT

Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP2 by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP2-synthesis. We tested the effects of the verified scarcity of PIP2 on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP2 in pull-down assays. On decreased PIP2 availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP2 reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP2. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP2-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP2 binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.


Subject(s)
Amphetamine/pharmacology , Phosphatidylinositol 4,5-Diphosphate/metabolism , Serotonin Plasma Membrane Transport Proteins/drug effects , HEK293 Cells , Humans , Second Messenger Systems , Serotonin Plasma Membrane Transport Proteins/genetics
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