Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

多巴胺 D ₃受体 (D ₃ R) 与多种精神病症状有关。增加D ₃ R 相对于多巴胺D ₂受体(D ₂ R)的选择性将有利于抗精神病治疗。在此，新型咔唑和四氢咔啉衍生物被报道为D ₃ R选择性配体。通过基于结构的虚拟筛选，ZLG-25（D ₃ R K _i = 685 nmol/L；D ₂ R K _i > 10,000 nmol/L）被鉴定为具有咔唑支架的新型D ₃ R选择性双位配体。支架跳跃导致了具有四氢-β-咔啉或四氢-γ-咔啉核心的新型D ₃ R-选择性类似物的发现。进一步的功能研究表明，大多数衍生物可作为 hD ₃ R 选择性拮抗剂。几种先导化合物可以剂量依赖性地抑制 MK-801 诱导的多动症。进一步的研究表明， 23j和36b可以减少阿扑吗啡引起的攀爬，而不会出现惊厥反应。此外， 36b在强迫游泳测试和悬尾测试中表现出不寻常的抗抑郁样活性，并减轻了 MK-801 引起的小鼠新物体识别的破坏。此外，初步研究证实了小鼠体内良好的 PK/PD 曲线、体重没有增加且血清催乳素水平有限。这些结果表明， 36b为具有多种抗精神病药样特性的新型抗精神病药物提供了潜在的机会。