Novel multi-target ligands of dopamine and serotonin receptors for the treatment of schizophrenia based on indazole and piperazine scaffolds-synthesis, biological activity, and structural evaluation

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 38; no. 1; p. 2209828
• Main Authors: Stępnicki, Piotr, Wronikowska-Denysiuk, Olga, Zięba, Agata, Targowska-Duda, Katarzyna M., Bartyzel, Agata, Wróbel, Martyna Z., Wróbel, Tomasz M., Szałaj, Klaudia, Chodkowski, Andrzej, Mirecka, Karolina, Budzyńska, Barbara, Fornal, Emilia, Turło, Jadwiga, Castro, Marián, Kaczor, Agnieszka A.
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.12.2023; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Antipsychotic; Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacology; Antipsychotics; Biochemistry & Molecular Biology; Biological activity; Chemistry; Chemistry, Medicinal; Chronic illnesses; Dopamine; Dopamine - therapeutic use; Dopamine D2 receptors; Drugs; G protein-coupled receptors; GPCR; Hallucinations; Humans; Indazoles; Life Sciences & Biomedicine; Ligands; Mental disorders; Molecular modelling; multi-target ligands; Pharmaceuticals; Pharmacology & Pharmacy; Pharmacy; Piperazine; Piperazine - pharmacology; Psychotropic drugs; Receptor, Serotonin, 5-HT1A - therapeutic use; Receptors, Serotonin; Research Paper; Schizophrenia; Schizophrenia - drug therapy; Science & Technology; Serotonin; Serotonin - therapeutic use; Serotonin S1 receptors; Serotonin S2 receptors; ANTIDEPRESSANT; EFFICACY; 5-HT1A RECEPTORS; ANXIETY; CRYSTAL-STRUCTURE; schizophrenia; CONFORMATION; PARAMETERS; multi-target ligands; NUCLEUS; PHARMACOLOGY; Antipsychotic; GPCR; INSIGHTS
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2023.2209828

Schizophrenia is a chronic mental disorder that is not satisfactorily treated with available antipsychotics. The presented study focuses on the search for new antipsychotics by optimising the compound D2AAK3, a multi-target ligand of G-protein-coupled receptors (GPCRs), in particular D 2 , 5-HT 1A , and 5-HT 2A receptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds 1-16 were designed, synthesised, and subjected to further evaluation. Their affinities for the above-mentioned receptors were assessed in radioligand binding assays and efficacy towards them in functional assays. Compounds 1 and 10, selected based on their receptor profile, were subjected to in vivo tests to evaluate their antipsychotic activity, and effect on memory and anxiety processes. Molecular modelling was performed to investigate the interactions of the studied compounds with D 2 , 5-HT 1A , and 5-HT 2A receptors on the molecular level. Finally, X-ray study was conducted for compound 1, which revealed its stable conformation in the solid state.