- Focus on Human Monoamine Transporter Selectivity. New Human DAT and NET Models, Experimental Validation, and SERT Affinity Exploration
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The most commonly used antidepressant drugs are the serotonin transporter inhibitors. Their effects depend strongly on the selectivity for a single monoamine transporter compared to other amine transporters or receptors, and the selectivity is roughly influenced by the spatial protein structure. Here, we provide a computational study on three human monoamine transporters, i.e., DAT, NET, and SERT. Starting from the construction of hDAT and hNET models, whose three-dimensional structure is unknown, and the prediction of the binding pose for 19 known inhibitors, 3D-QSAR models of three human transporters were built. The training set variability, which was high in structure and activity profile, was validated using a set of in-house compounds. Results concern more than one aspect. First of all, hDAT and hNET three-dimensional structures were built, validated, and compared to the hSERT one; second, the computational study highlighted the differences in binding site arrangement statistically correlated to inhibitor selectivity; third, the profiling of new inhibitors pointed out a conservation of the inhibitory activity trend between rabbit and human SERT with a difference of about 1 order of magnitude; fourth, binding and functional studies confirmed 4-(benzyloxy)-4-phenylpiperidine 20a-d and 21a-d as potent SERT inhibitors. In particular, one of the compounds (compound 20b) revealed a higher affinity for SERT than paroxetine in human platelets.
- Ortore, Gabriella,Orlandini, Elisabetta,Betti, Laura,Giannaccini, Gino,Mazzoni, Maria Rosa,Camodeca, Caterina,Nencetti, Susanna
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Read Online
- HEPATITIS B ANTIVIRAL AGENTS
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The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.
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Page/Page column 212
(2013/07/05)
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- Synthesis and SAR study of 4-arylpiperidines and 4-aryl-1,2,3,6- tetrahydropyridines as 5-HT2C agonists
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A series of substituted 4-arylpiperidines and a smaller family of 4-aryl-1,2,3,6-tetrahydropyridines were synthesized and their biological activity at the 5-HT2C receptor studied to determine whether either series showed noteworthy agonist activity. Structure-activity relationships were developed from the performed receptor binding assays and functional studies, and the results of the analysis are presented herein.
- Conway, Richard J.,Valant, Celine,Christopoulos, Arthur,Robertson, Alan D.,Capuano, Ben,Crosby, Ian T.
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supporting information; experimental part
p. 2560 - 2564
(2012/05/05)
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- Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists
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Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.
- Sasmal, Sanjita,Balaji, Gade,Kanna Reddy, Hariprasada R.,Balasubrahmanyam,Srinivas, Gujjary,Kyasa, Shivakumar,Sasmal, Pradip K.,Khanna, Ish,Talwar, Rashmi,Suresh,Jadhav, Vikram P.,Muzeeb, Syed,Shashikumar, Dhanya,Harinder Reddy,Sebastian,Frimurer, Thomas M.,Rist, ?ystein,Elster, Lisbeth,H?gberg, Thomas
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scheme or table
p. 3157 - 3162
(2012/06/04)
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- Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors
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With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measu
- Nencetti, Susanna,Mazzoni, Maria R.,Ortore, Gabriella,Lapucci, Annalina,Giuntini, Janette,Orlandini, Elisabetta,Banti, Irene,Nuti, Elisa,Lucacchini, Antonio,Giannaccini, Gino,Rossello, Armando
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experimental part
p. 825 - 834
(2011/04/18)
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- Structural changes of benzylether derivatives of vesamicol and their influence on the binding selectivity to the vesicular acetylcholine transporter
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18F labelled vesamicol analogues, which bind to the vesicular acetylcholine transporter (VAChT) in central cholinergic nerve terminals, are expected to be potential radioligands for the visualisation of cholinergic transmission deficits via pos
- Wenzel, Barbara,Sorger, Dietlind,Heinitz, Katrin,Scheunemann, Matthias,Schliebs, Reinhard,Steinbach, J?rg,Sabri, Osama
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p. 1197 - 1205
(2007/10/03)
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- Combination therapy for the treatment of benign prostatic hyperplasia
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This invention relates to combination therapy for the treatment of benign prostatic hyperplasia comprising an alpha-1a antagonist and an endothelin antagonist. More specifically, the use of a selective alpha-1a adrenergic receptor antagonist in combination with a subtype non-selective endothelin antagonist provides relief of lower urinary tract symptoms in patients with symptomatic prostatism or benign prostatic hyperplasia. This combination therapy improves lower urinary tract symptoms including increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism.
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- Pharmacophore-based discovery, synthesis, and biological evaluation of 4-phenyl-1-arylalkyl piperidines as dopamine transporter inhibitors
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Pharmacophore-based discovery, synthesis, and structure-activity relationship (SAR) of a series of 4-phenyl-1-arylalkyl piperidines are disclosed. These compounds have been evaluated for their ability to inhibit reuptake of dopamine (DA) into striatal nerve endings (synaptosomes). The lead compound 5 and the most potent analogue 43 were found to have significant functional antagonism.
- Sakamuri, Sukumar,Enyedy, Istvan J,Kozikowski, Alan P,Zaman, Wahiduz A,Johnson, Kenneth M,Wang, Shaomeng
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p. 495 - 500
(2007/10/03)
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- Oxazolidinones as alpha 1A receptor antagonists
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This invention is directed to oxazolidinone compounds which are selective antagonists for human alpha 1A receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where the antagonism of the alpha 1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
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- σ Ligands with subnanomolar affinity and preference for the σ2 binding site. 1. 3-(ω-Aminoalkyl)-1H-indoles
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A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines, 4- phenyl-1,2,3,6-terrahydropyridines, and 4-phenylpiperazines was synthesized. The phenyl group was optionally substituted with 4-fluoro or 2-methoxy substituents. High affinity for both σ1 and σ1 binding sites was achieved with these compounds. Additionally, these compounds had relatively high affinity for serotonin 5-HT(1A) and 5-HT(2A), dopamine D2, and adrenergic α1 receptors. Introduction of a 4-fluorophenyl substituent at the indole nitrogen atom rendered very selective σ2 ligands with subnanomolar affinity for the σ2 binding site. The prototype of such a compound was 1-(4- fluorophenyl)-3-[4-[4-(4-fluorophenyl)-1-piperidinyl]-1-butyl]-1H-indole, 11a (code no. Lu 29-253). This compound had the following binding affinities: IC50 (σ1) = 16 nM, IC50 (σ2) = 0.27 riM, IC50 (5-HT(1A)) = 22 000 nM, IC50 (5-HT(2A)) = 270 nM, IC50 (D2) = 4200 nM, IC50 (α1) = 220nM. Spiro-joining of the phenyl and the piperidine rings into a spiro[isobenzofuran-1(3H),4'-piperidinel ring system resulted in even more selective compounds. Variations of the 1-substituent at the indole and of the chain length of the alkylene spacer group were studied. The optimal compound was the spiro analogue of compound 11a. This compound is 1'-14-[1(4- fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4'- piperidine], 14f (code no. Lu 28-179), with the binding affinities: IC50 (σ1) = 17 nM, IC50 (σ2) = 0.12 nM, IC50 (5-HT(1A)) = 21 000 nM, IC50 (5-HT(2A)) = 2000 nM, IC50 (D2) = 800 nM, IC50 (α1) = 330 nM. However, the most selective σ2 versus σ1 ligand was the tropane derivative 1-(4-fluorophenyl)-3-[4-[3-(4-fluorophenyl)-8- azabicyclo[3.2.1]oct-2-en-8-yl]-1-butyl]-1H-indole, 15a. This compound had the following binding affinities: IC50 (σ1) = 1200 nM, IC50 (σ2) = 2.5 nM. Potent anxiolytic activity in the black/white box exploration test in rats was found with the two most prominent σ2 ligands Lu 29-253 and Lu 28- 179. Good penetration into the CNS was documented both after subcutaneous and peroral administration of Lu 28-179 by ex vivo binding studies. Long duration of action was demonstrated both in ex vivo binding (T(1/2) ~ 20 h) and in the black/white box exploration test.
- Perregaard,Moltzen,Meier,Sanchez
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p. 1998 - 2008
(2007/10/02)
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- Synthesis and dopaminergic activity of some 3-(1,2,3,6-tetrahydro-1- pyridylalkyl)indoles. A novel conformational model to explain structure- activity relationships
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The synthesis and dopaminergic properties of a novel type of dopamine agonist is described. The number and kind of essential structural elements differ significantly from that of the rigid apomorphine-type dopamine agonists. Using standard molecular modeling techniques, a conformational model is developed proposing a U-shaped conformation which might be energetically preferred through aromatic π-π-interactions between both of the electron rich aromatic structural elements of this class of compounds. Superimposition of conformations of the lead compound 28 with apomorphine yields a novel model explaining the atypical structure-activity relationships found in this class of indolealkylamines.
- Bottcher,Barnickel,Hausberg,Haase,Seyfried,Eiermann
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p. 4020 - 4026
(2007/10/02)
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