| 1. |
- Bartuzi, Damian, et al.
(författare)
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Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes
- 2022
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Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT(2A)R interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.
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| 2. |
- Kaczor, Agnieszka A., et al.
(författare)
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Allosteric Modulators of Dopamine D-2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases : Overview, Pharmacology, Structural Aspects and Synthesis
- 2023
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Ingår i: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 28:1
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Forskningsöversikt (refereegranskat)abstract
- 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 D-2 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 D-2 receptor modulators is presented, ranging from their pharmacology and structural aspects of ligand-receptor interactions to their synthesis.
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| 3. |
- Stepnicki, Piotr, et al.
(författare)
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Development and Characterization of Novel Selective, Non-Basic Dopamine D-2 Receptor Antagonists for the Treatment of Schizophrenia
- 2023
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 28:10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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