Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland.
Independent Laboratory of Behavioral Studies, Chair of Biomedical Sciences, Faculty of Biomedicine, Medical University of Lublin, Lublin, Poland.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2209828. 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, 5-HT, and 5-HT receptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds - 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 and , selected based on their receptor profile, were subjected to 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, 5-HT, and 5-HT receptors on the molecular level. Finally, X-ray study was conducted for compound , which revealed its stable conformation in the solid state.
精神分裂症是一种慢性精神障碍，目前可用的抗精神病药物对此治疗效果并不理想。本研究专注于通过优化多靶点配体 D2AAK3（G 蛋白偶联受体（GPCR）的化合物，特别是 D、5-HT 和 5-HT 受体）来寻找新的抗精神病药物。这种受体谱可能有益于治疗精神分裂症。设计、合成了化合物-，并对其进行了进一步评估。在放射配体结合试验中评估了它们对上述受体的亲和力，并在功能试验中评估了它们的疗效。基于受体谱选择化合物-进行-测试，以评估其抗精神病活性以及对记忆和焦虑过程的影响。进行了分子建模以研究研究化合物与 D、5-HT 和 5-HT 受体在分子水平上的相互作用。最后，对化合物进行了 X 射线研究，揭示了其在固态下的稳定构象。
