| Title: | "Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D(2) Receptor Ligand" |
| Author(s): | Kondej M; Bartyzel A; Pitucha M; Wrobel TM; Silva AG; Matosiuk D; Castro M; Kaczor AA; |
| Address: | "Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland. magda.kondej@onet.pl. Department of General and Coordination Chemistry, Maria Curie-Sklodowska University, M. Curie-Sklodowskiej Sq. 2, PL-20031 Lublin, Poland. agata.bartyzel@poczta.umcs.lublin.pl. Independent Radiopharmacy Unit, Department of Organic Chemistry, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland. monika.pitucha@umlub.pl. Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland. tomasz.wrobel@umlub.pl. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen O, Denmark. tomasz.wrobel@umlub.pl. Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de Compostela, Spain. andrea.garcia.silva@rai.usc.es. Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland. dariusz.matosiuk@umlub.pl. Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de Compostela, Spain. marian.castro@usc.es. Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland. agnieszka.kaczor@umlub.pl. School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland. agnieszka.kaczor@umlub.pl" |
| DOI: | 10.3390/molecules23092249 |
| ISSN/ISBN: | 1420-3049 (Electronic) 1420-3049 (Linking) |
| 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 D(2) receptor with K(i) 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 P2(1)2(1)2(1). The compound has a non-planar conformation. The studied compound was docked to the novel X-ray structure of the human dopamine D(2) 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: CO(2); H(2)O toluene and CO while in the case of pyrolysis process in the FTIR spectra; the characteristic bands of NH(3); piperidine and indole are additionally observed" |
| Keywords: | "Binding, Competitive Calorimetry, Differential Scanning Crystallography, X-Ray Humans Hydrogen Bonding Indoles/*chemical synthesis/*chemistry Ligands Molecular Conformation Molecular Docking Simulation Pyrrolidines/*chemical synthesis/*chemistry Receptors;" |
| Notes: | "MedlineKondej, Magda Bartyzel, Agata Pitucha, Monika Wrobel, Tomasz M Silva, Andrea G Matosiuk, Dariusz Castro, Marian Kaczor, Agnieszka A eng 2017/27/B/NZ7/01767/Narodowe Centrum Nauki/ Switzerland 2018/09/06 Molecules. 2018 Sep 4; 23(9):2249. doi: 10.3390/molecules23092249" |
