Recent advances in dopamine D<sub>2</sub> receptor ligands in the treatment of neuropsychiatric disorders
Radomír Jůza, Kamil Musílek, Eva Mezeiová, Ondřej Soukup, Jan Korábečný
Abstract
Abstract Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D 1–5 Rs), which belong to the G protein‐coupled receptor family. Antagonists and partial agonists of D 2 Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D 2 R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4‐(2,3‐dichlorophenyl), 4‐(2‐methoxyphenyl)‐, 4‐(benzo[ b ]thiophen‐4‐yl)‐1‐substituted piperazine, and 4‐(6‐fluorobenzo[ d ]isoxazol‐3‐yl)piperidine moieties are critical for high D 2 R affinity. Four to six atoms chains are optimal for D 2 R affinity with 4‐butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D 2 R affinity. In this review, we provide a thorough overview of the therapeutic potential of D 2 R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D 2 R ligands, which have been developed in the last decade (2010–2021), and belong to the 1,4‐disubstituted aromatic cyclic amine group. Due to the abundance of data, allosteric D 2 R ligands and D 2 R modulators from patents are not discussed in this review.