Search

The dopamine D2 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 D2 receptor is the main target for the drugs used. In this work, we aimed at discovering new selective D2 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 D2 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 D2 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. [ABSTRACT FROM AUTHOR]

Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. Allosteric modulators, i.e., compounds which bind in a receptor site topologically distinct from orthosteric sites, exhibit a number of advantages. They are more selective, safer and display a ceiling effect which prevents overdosing. Allosteric modulators of dopamine D2 receptor are potential drugs against a number of psychiatric and neurological diseases, such as schizophrenia and Parkinson's disease. In this review, an insightful summary of current research on D2 receptor modulators is presented, ranging from their pharmacology and structural aspects of ligand-receptor interactions to their synthesis. [ABSTRACT FROM AUTHOR]

Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin 5-HT1A and 5-HT2A receptor ligands. X-ray studies revealed that the D2AAK5 compound crystallizes in centrosymmetric triclinic space group with one molecule in the asymmetric unit. The main interaction between the ligands and the receptors is the salt bridge between the protonatable nitrogen atom of the ligands and the conserved Asp (3.32) of the receptors. The complexes were stable in the molecular dynamic simulations. MD revealed that the studied ligands are relatively stable in their binding sites, with the exception of D2AAK7 in the serotonin 5-HT1A receptor. D2AAK7 exerts anxiolytic activity in the EPM test, while D2AAK5 has a beneficial effect on the memory processes in the PA test. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A series of urea derivatives bearing nitroaryl moiety has been synthesized and assayed for their potential antiproliferative activities. Some of the tested compounds displayed activity in RK33 laryngeal cancer cells and TE671 rhabdomyosarcoma cells while being generally less toxic to healthy HSF human fibroblasts cells. One compound was demonstrated to be a moderate CDK2 inhibitor with IC50 = 14.3 µM. Its structure was solved by an X-ray crystallography and molecular modelling was performed to determine structure-activity relationship. Obtained compounds constitute novel structures and generally demonstrated greater cytotoxicity in comparison to cisplatin. This study offers new structural motifs with potential for further development. [ABSTRACT FROM AUTHOR]

Six novel imidazoline derivatives were synthesized and tested in antifungal assays. One of the compounds, N-cyclohexyl-2-imino-3-(4-nitrophenyl)imidazolidine-1-carboxamide showed moderate activity against several clinical strains of Candida albicans. Its structure was solved by X-ray crystallography and its mode of action was deduced using molecular modelling. It was found to be similar to that of fluconazole. The potential for further optimization including SAR of the compound is briefly discussed. [ABSTRACT FROM AUTHOR]

The 5-HT 2A receptor is a molecular target of high pharmacological importance. Ligands of this protein, particularly atypical antipsychotics, are useful in the treatment of numerous mental disorders, including schizophrenia and major depressive disorder. Structure-based virtual screening using a 5-HT 2A receptor complex was performed to identify novel ligands for the 5-HT 2A receptor, serving as potential antidepressants. From the Enamine screening library, containing over 4 million compounds, 48 molecules were selected for subsequent experimental validation. These compounds were tested against the 5-HT 2A receptor in radioligand binding assays. From the tested batch, six molecules were identified as ligands of the main molecular target and were forwarded to a more detailed in vitro profiling. This included radioligand binding assays at 5-HT 1A , 5-HT 7 , and D 2 receptors and functional studies at 5-HT 2A receptors. These compounds were confirmed to show a binding affinity for at least one of the targets tested in vitro. The success rate for the inactive template-based screening reached 17 %, while it was 9 % for the active template-based screening. Similarity and fragment analysis indicated the structural novelty of the identified compounds. Pharmacokinetics for these molecules was determined using in silico approaches., (© 2024 Wiley-VCH GmbH.)

Metastable binding sites (MBS) have been observed in a multitude of molecular dynamics simulations and can be considered low affinity allosteric binding sites (ABS) that function as stepping stones as the ligand moves toward the orthosteric binding site (OBS). Herein, we show that MBS can be utilized as ABS in ligand design, resulting in ligands with improved binding kinetics. Four homobivalent bitopic ligands ( 1 - 4 ) were designed by molecular docking of ( S )-alprenolol (( S )-ALP) in the cocrystal structure of the β 2 adrenergic receptor (β 2 AR) bound to the antagonist ALP. Ligand 4 displayed a potency and affinity similar to ( S )-ALP, but with a >4-fold increase in residence time. The proposed binding mode was confirmed by X-ray crystallography of ligand 4 in complex with the β 2 AR. This ligand design principle can find applications beyond the β 2 AR and G protein-coupled receptors (GPCRs) as a general approach for improving the pharmacological profile of orthosteric ligands by targeting the OBS and an MBS simultaneously.

Herein, we report the development of bitopic ligands aimed at targeting the orthosteric binding site (OBS) and a metastable binding site (MBS) within the same receptor unit. Previous molecular dynamics studies on ligand binding to the β 2 -adrenergic receptor (β 2 AR) suggested that ligands pause at transient, less-conserved MBSs. We envisioned that MBSs can be regarded as allosteric binding sites and targeted by homobivalent bitopic ligands linking two identical pharmacophores. Such ligands were designed based on docking of the antagonist ( S )-alprenolol into the OBS and an MBS and synthesized. Pharmacological characterization revealed ligands with similar potency and affinity, slightly increased β 2 /β 1 AR-selectivity, and/or substantially slower β 2 AR off-rates compared to ( S )-alprenolol. Truncated bitopic ligands suggested the major contribution of the metastable pharmacophore to be a hydrophobic interaction with the β 2 AR, while the linkers alone decreased the potency of the orthosteric fragment. Altogether, the study underlines the potential of targeting MBSs for improving the pharmacological profiles of ligands.