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The dopamine D-2 receptor, which belongs to the family of G protein-coupled receptors (GPCR), is an important and well-validated drug target in the field of medicinal chemistry due to its wide distribution, particularly in the central nervous system, and involvement in the pathomechanism of many disorders thereof. Schizophrenia is one of the most frequent diseases associated with disorders in dopaminergic neurotransmission, and in which the D-2 receptor is the main target for the drugs used. In this work, we aimed at discovering new selective D-2 receptor antagonists with potential antipsychotic activity. Twenty-three compounds were synthesized, based on the scaffold represented by the D2AAK2 compound, which was discovered by our group. This compound is an interesting example of a D-2 receptor ligand because of its non-classical binding to this target. Radioligand binding assays and SAR analysis indicated structural modifications of D2AAK2 that are possible to maintain its activity. These findings were further rationalized using molecular modeling. Three active derivatives were identified as D-2 receptor antagonists in cAMP signaling assays, and the selected most active compound 17 was subjected to X-ray studies to investigate its stable conformation in the solid state. Finally, effects of 17 assessed in animal models confirmed its antipsychotic activity in vivo.

In this work we report new discrete mononucler heteroleptic zinc(II) halido complexes of the type [Zn(Hal) 2 HL] (Hal = Cl, 1 ; Br, 2 ) and zinc(II) pseudohalido complex [Zn(NCS) 2 HL] ·1.5MeOH ( 3 ·1.5MeOH) ( HL = 2-formylpyridine nicotinoyl hydrazone). Single crystal X-ray diffraction revealed that in the struc- tures of complexes 1–3 , the Zn(II) metal atom is in a five-coordinated coordination environment and adopts a distorted square pyramidal chromophore, formed by one N 2 O tridentate chelator HL and two halides or thiocyanates, respectively. All complexes display a very similar molecular structure and com- plexes 1 and 2 are fully isostructural. Crystal packing of 1 and 2 is mainly dictated by the bifurcated N–H ···Hal and linear C–H ···Hal hydrogen bonds, yielding 1D polymeric chains, which additionally stabilized by intermolecular stacking interactions of the types ZnOCNN ···ZnOCNN, ZnOCNN ···ZnNCCN and 2-Py ···3- Py. These 1D chains are interlinked into a 3D network through C–H ···Hal interactions. Crystal packing of 3 ·1.5MeOH is constructed from centrosymmetric dimers formed through linear N–H ···O and O–H ···N hy- drogen bonds, yielding a hydrogen bonded synthon of motif R 4 4 (16). These dimers are interlinked trough the C–S ···ZnNCCN interactions, yielding 1D polymeric chains, which, in turn, are interlinked through the C–H ···O bonds, and ZnNCCN ···3-Py and 3-Py ···3-Py stacking interactions into a 3D framework. Hirshfeld surface analysis, employed to gain additional insight into interactions responsible for the packing of com- plexes, and quantitative examination of 2D fingerprint plots revealed that the most important factors in the crystal packing are H ···Hal and and H ···H contacts in 1 and 2 , and H ···H, H ···N, H ···C and H ···S contacts in 3 , further supported by C ···C contacts. Density function theory (DFT) calculations were performed to gather more information into structure and bonding since they play an important role in the construct

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

Background: Blockade of kainate receptors is an emerging strategy to treat neurodegenera-tive diseases, including Parkinson’s disease as well as to treat epilepsy. In particular, non-competitive antagonists of kainate receptors are promising due to the expected good safety profile. We present here synthesis, experimental and computational studies of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)benzamide which is an intermediate in the synthesis of hypoxanthine derivatives which were designed as non-competitive antagonists of kainate GluK1/GluK2 receptors. Method: The title compound was obtained in a five-step synthesis protocol and characterized used X-ray crystallography and experimental and computed spectra. Results: The presented detailed X-ray studies of the title compound confirm the reaction course. The title compound crystallizes in triclinic P-1 space group. The asymmetric unit comprises two independent molecules of the compound (A and B) and a DMF solvent molecule. The interpretation of IR spectra was facilitated by Potential Energy Distribution (PED) analysis. The low value of HOMO-LUMO gap indicates that the studied compound is relatively reactive. Conclusion: The title compound is a well-characterized intermediate which will be subjected to cycli-zation to hypoxanthine derivative designed as non-competitive antagonist of kainate GluK1 and GluK2 receptors.