Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor

Jóźwiak, Krzysztof; Targowska-Duda, Katarzyna M.; Kaczor, Agnieszka A.; Kozak, Joanna; Ligeza, Agnieszka; Szacoń, Elżbieta; Wróbel, Tomasz M.; Budzyńska, Barbara; Biała, Grażyna; Fornal, Emilia; Poso, Antti; Wainer, Irving W.; Matosiuk, Dariusz

doi:10.1016/j.bmc.2014.10.036

Cited by 8 publications

(15 citation statements)

References 31 publications

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“…Molecular dynamics studies of the ligand-receptor complex were performed using Desmond [ 50 ] incorporated in Schrödinger suite of software [ 51 ] as described previously [ 52 , 53 , 54 ]. The complex was inserted into POPC membrane, hydrated and ions were added to neutralize protein charges and then to the concentration of 0.15 M NaCl [ 55 ].…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

et al. 2018

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Compound D2AAK1_3 was designed as a modification of the lead structure D2AAK1 (an in vivo active multi-target compound with nanomolar affinity to a number of aminergic GPCRs) and synthesized in the reaction of 5-ethoxyindole and 1-benzyl-4-piperidone. This compound has an affinity to the human dopamine D2 receptor with Ki of 151 nM. The aim of these studies was the structural and thermal characterization of the compound D2AAK1_3. In particular; X-ray studies; molecular docking and molecular dynamics as well as thermal analysis were performed. The studied compound crystallizes in orthorhombic system; in chiral space group P212121. The compound has a non-planar conformation. The studied compound was docked to the novel X-ray structure of the human dopamine D2 receptor in the inactive state (PDB ID: 6CM4) and established the main contact between its protonatable nitrogen atom and Asp (3.32) of the receptor. The obtained binding pose was stable in molecular dynamics simulations. Thermal stability of the compound was investigated using the TG-DSC technique in the air atmosphere, while TG-FTIR analyses in air and nitrogen atmospheres were also performed. The studied compound is characterized by good thermal stability. The main volatile products of combustion are the following gases: CO2; H2O toluene and CO while in the case of pyrolysis process in the FTIR spectra; the characteristic bands of NH3; piperidine and indole are additionally observed.

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Section: Methodsmentioning

confidence: 99%

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

et al. 2018

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“…Molecular dynamics studies of ligand–receptor complexes were performed using Desmond v. 3.0.3.1 [ 37 ] and OPLS force field as described previously [ 38 , 39 ]. The complexes were inserted into the POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membrane, hydrated, and ions were added to neutralize protein charges and then to the reaching of a concentration of 0.15 M NaCl.…”

Section: Methodsmentioning

confidence: 99%

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics

2016

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In order to apply structure-based drug design techniques to G protein-coupled receptor complexes, it is essential to model their 3D structure and to identify regions that are suitable for selective drug binding. For this purpose, we have developed and tested a multi-component protocol to model the inactive conformation of the dopamine D2 receptor dimer, suitable for interaction with homobivalent antagonists. Our approach was based on protein–protein docking, applying the Rosetta software to obtain populations of dimers as present in membranes with all the main possible interfaces. Consensus scoring based on the values and frequencies of best interfaces regarding four scoring parameters, Rosetta interface score, interface area, free energy of binding and energy of hydrogen bond interactions indicated that the best scored dimer model possesses a TM4–TM5–TM7–TM1 interface, which is in agreement with experimental data. This model was used to study interactions of the previously published dopamine D2 receptor homobivalent antagonists based on clozapine,1,4-disubstituted aromatic piperidines/piperazines and arylamidoalkyl substituted phenylpiperazine pharmacophores. It was found that the homobivalent antagonists stabilize the receptor-inactive conformation by maintaining the ionic lock interaction, and change the dimer interface by disrupting a set of hydrogen bonds and maintaining water- and ligand-mediated hydrogen bonds in the extracellular and intracellular part of the interface.Graphical AbstractStructure of the final model of the dopamine D2 receptor homodimer, indicating the distancebetween Tyr37 and Tyr 5.42 in the apo form (left) and in the complex with the ligand (right).Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-016-3065-2) contains supplementary material, which is available to authorized users.

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“…Molecular dynamics studies of selected ligand-receptor complexes were performed using Desmond v. 3.0.3.1 (Bowers et al 2006) as described previously Jozwiak et al 2014;Kaczor et al 2016a, c). The complexes were inserted into POPC (1-palmitoyl-2-oleoylsn-glycero-3-phosphocholine) membrane, hydrated and ions were added to neutralize protein charges and then to the concentration of 0.15 M NaCl.…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

et al. 2016

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The dopaminergic hypothesis of schizophrenia is the main concept explaining the direct reasons of schizophrenia and the effectiveness of current antipsychotics. All antipsychotics present on the market are potent dopamine D 2 receptor antagonists or partial agonists. In this work we investigate a series of dopamine D 2 receptor antagonists which do not fulfill the criteria of the classical pharmacophore model as they do not possess a protonatable nitrogen atom necessary to interact with the conserved Asp(3.32). Such compounds are interesting, inter alia, due to possible better pharmacokinetic profile when compared to basic, ionizable molecules. By means of homology modeling, molecular docking and molecular dynamics we determined that the compounds investigated interact with Asp(3.32) via their amide nitrogen atom. It was found that the studied compounds stabilize the receptor inactive conformation through the effect on the ionic lock, which is typical for GPCR antagonists. We constructed a CoMFA model for the studied compounds with the following statistics:63. The quality of the CoMFA model was confirmed by high value of R 2 of the test set, equal 0.96. The CoMFA model indicated two regions where bulky substituents are favored and two regions where bulky substituents are not beneficial. Two red contour regions near carbonyl groups were identified meaning that negative charge would be favored here. Furthermore, the S-oxide group is connected with blue contour region meaning that positive charge is favored in this position. These findings may be applied for further optimization of the studied compound series.

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Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor

Cited by 8 publications

References 31 publications

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

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