Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor

Abstract

A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands.

Confinement Effects in Protonation Reactions Catalyzed by Zeolites with Large Void Structures

“…In previous studies of chemical reactions of interest in the zeolite chemistry, we demonstrated the usefulness of quantum theory of atoms in molecules (QTAIMs) analysis and the relevance of the information that can be obtained through the analysis of electron density distribution. − One of the advantages of the QTAIM methodology over other global measures of the interaction energy is that it allows one to decompose the interaction energy in contributions by an atom or a group of atoms, and because of which it was used in the analysis, design, and optimization of ligand molecules in the ligand/receptor recognition process . Similar analysis could be applied in the study of adsorbate–catalyst interactions, which makes it particularly useful for these catalytic systems where several interactions are found.…”

“…22−25 One of the advantages of the QTAIM methodology over other global measures of the interaction energy is that it allows one to decompose the interaction energy in contributions by an atom or a group of atoms, and because of which it was used in the analysis, design, and optimization of ligand molecules in the ligand/receptor recognition process. 26 Similar analysis could be applied in the study of adsorbate−catalyst interactions, which makes it particularly useful for these catalytic systems where several interactions are found.…”

Combining Charge Density Analysis with Machine Learning Tools To Investigate the Cruzain Inhibition Mechanism

“…We have previously applied this theory to understand the action mechanism of human dihydrofolate reductase inhibitors, , BACE1 inhibitors, , D2 dopamine receptor ligands, − sphingosine kinase 1 (Sphk1) inhibitors, and HIV-1 protease flap fragments, among others.…”

Evaluating the conformational space of the active site of D2 dopamine receptor. Scope and limitations of the standard docking methods

“…There are numerous advantages to select such compounds: (a) they are compounds of great interest in medicinal chemistry, (b) reliable structural data are available for the molecular target (D2DR), [21] (c) data on biological activities are available for these ligands acting on D2DR, [22] (d) we have previously studied DA interacting in the active site of D2DR; [23] in addition, we have reported new ligands for this receptor, some of them very powerful and selective with respect to D1DR. [24][25][26] In other words, we have experience in this molecular target (e) the structural characteristic of these ligands allows to perform a systematic conformational study since their conformations are mainly determined by two dihedral angles (ϕ and ψ in Figure 1), (f) from a structural point of view they represent adequately ligands of complexes type (ii) since they are flexible but at the same time they have only three dihedral angles, being two of them the determinants of the spatial ordering, (g) structural differences between the ligands are convenient, in fact they are phenylethylamines with different hydroxylation patterns; note that PEA does not have hydroxyl groups in its structure, dopamine has two of them from its catechol ring, while m-OH-PEA has only one phenolic hydroxyl in meta position. The advantage of using structurally closely related compounds is that the effects of small structural changes on the properties of the compounds may then be determined.…”