Abstract
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.
Highlights
Dopamine receptors belong to rhodopsin-like, aminergic G protein-coupled receptors (GPCRs)Dopamine receptors to rhodopsin-like, aminergic protein-coupled receptors receptors (GPCRs) and play a crucial role in belong the central nervous system.There areGfive subtypes of dopamine and play a crucial role in the central nervous system.There are five subtypes of dopamine receptors (D1, D2, D3, D4 and D5) which can be divided into the two groups D1-like (D1 and D5) and D2-like (D2, (DD2, D can be divided into theoftwo groups D1 -like (D1 andcyclic D5 ) and D2 -like 4 and D5 ) which D31,andD34,) Ddepending on activation or inhibition a secondary messenger, adenosine
We identified potentially screening aimed at identifying dopamine
D2AAK1_3 is a new compound and it is an analogue of known tetrahydropyridin-4-yl)-1H-indole and 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1Hindole
Summary
Dopamine receptors belong to rhodopsin-like, aminergic G protein-coupled receptors (GPCRs). Dopamine receptors to rhodopsin-like, aminergic protein-coupled receptors receptors (GPCRs) and play a crucial role in belong the central nervous system. In the thesearch search novel potential antipsychotics, we performed structure-based virtual aimed at identifying dopamine receptor antagonists [14]. Is a promising multi-target structure with to a number of dopamine and serotonin receptors with antipsychotic, anxiolytic and procognitive nanomolar affinity to a number of dopamine and serotonin receptors with antipsychotic, anxiolytic activity in vivo [15]. (Figure detailed experimental and computational structural as well as thermal studies for this compound. 1) and performed detailed experimental and computational structural as well as thermal studies for this. (3) describing ligand-receptor interactions at the molecular level to level design structure D2AAK1;.
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