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

TY - JOUR

T1 - 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

AU - Kondej, Magda

AU - Bartyzel, Agata

AU - Pitucha, Monika

AU - Wróbel, Tomasz

AU - Silva, Andrea

AU - Matosiuk, Dariusz

AU - Castro, Marián

AU - Kaczor, Agnieszka

PY - 2018/9/4

Y1 - 2018/9/4

N2 - 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.

AB - 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.

U2 - 10.3390/molecules23092249

DO - 10.3390/molecules23092249

M3 - Journal article

C2 - 30181442

SN - 1431-5157

VL - 23

JO - Molecules

JF - Molecules

IS - 9

M1 - 2249

ER -