Development and Characterization of Novel Selective, Non-Basic Dopamine D 2 Receptor Antagonists for the Treatment of Schizophrenia.

Autor: Stępnicki P; Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland., Wośko S; Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy, Faculty of Pharmacy, Medical University of Lublin, Chodźki 1, PL-20093 Lublin, Poland., Bartyzel A; Department of General and Coordination Chemistry and Crystallography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Skłodowska University in Lublin, Maria Curie-Skłodowska Sq. 2, PL-20031 Lublin, Poland., Zięba A; Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland., Bartuzi D; Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland.; Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, 75124 Uppsala, Sweden., Szałaj K; Department of Bioanalytics, Chair of Dietetics and Bioanalytics, Faculty of Biomedicine, Medical University of Lublin, Jaczewskiego 8b St., PL-20090 Lublin, Poland., Wróbel TM; Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland., Fornal E; Department of Bioanalytics, Chair of Dietetics and Bioanalytics, Faculty of Biomedicine, Medical University of Lublin, Jaczewskiego 8b St., PL-20090 Lublin, Poland., Carlsson J; Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, 75124 Uppsala, Sweden., Kędzierska E; Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland., Poleszak E; Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy, Faculty of Pharmacy, Medical University of Lublin, Chodźki 1, PL-20093 Lublin, Poland., Castro M; Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, Avda de Barcelona, E-15782 Santiago de Compostela, Spain.; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Travesía da Choupana s/n, E-15706 Santiago de Compostela, Spain., Kaczor AA; Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland.; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2023 May 20; Vol. 28 (10). Date of Electronic Publication: 2023 May 20.
DOI: 10.3390/molecules28104211
Abstrakt: 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.
Databáze: MEDLINE
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