Development of Selective Antagonists of Dopamine Receptor Subtypes for the Treatment of Schizophrenia

다국어 초록 (Multilingual Abstract)

The discovery of new ligands with affinity and selectivity for the dopamine receptor subtypes is an important area in medicinal chemistry. Classical dopamine D₂ antagonists are effective in treating schizophrenia. However, they cause severe extrapyramidal side effects that are thought to result from the blockade of D₂ receptors in the striatum of brain. In early 1990, the discovery of dopamine D₃ and D₄ receptor and their distribution in the limbic areas of brain suggests that these receptors may be particularly an attractive target for the design of potential selective antipsychotic drugs without causing extrapyramidal side effects. The discovery of new ligands with affinity and selectivity for the dopamine receptor subtypes is an important subject in fields of medicinal chemistry.
In this study, we designed and synthesized pyrazole analogues coupled with the phenyl piperazine system for the discovery of new antipsychotic compound to be active at dopamine receptors. A phenylpiperazinylalkylpyrazole library was constructed through the parallel solution-phase synthetic approach. A small synthesized library consists of 200 pyrazole analogues was biologically evaluated for dopamine receptors. Several compounds showed selectively high affinity for dopamine receptor subtypes. Also, selected compounds were evaluated in vivo study.