Gao Run-Duo, Taylor Michelle, McInnis Tamara, Chen Zhenglan, Gori Sadakatali S, LaPorte Heather M, Siegler Maxime A, Neisewander Janet L, Mach Robert H, Singh Meharvan, Slusher Barbara S, Rais Rana, Luedtke Robert R, Tsukamoto Takashi
Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
ACS Chem Neurosci. 2023 Mar 1;14(5):947-957. doi: 10.1021/acschemneuro.2c00791. Epub 2023 Feb 13.
Reduced haloperidol () was previously reported to act as a potent sigma-1 receptor (S1R) ligand with substantially lower affinity to the dopamine D2 receptor (D2R) compared to haloperidol. It was also found to facilitate brain-derived neurotrophic factor (BDNF) secretion from astrocytic glial cell lines in a sigma-1 receptor (S1R)-dependent manner. Although an increase in BDNF secretion may have beneficial effects in some neurological conditions, the therapeutic utility of reduced haloperidol () is limited because it can be oxidized back to haloperidol in the body, a potent dopamine D2 receptor antagonist associated with well-documented adverse effects. A difluorinated analogue of reduced haloperidol, (±)-4-(4-chlorophenyl)-1-(3,3-difluoro-4-(4-fluorophenyl)-4-hydroxybutyl)piperidin-4-ol (), was synthesized in an attempt to minimize the oxidation. Compound (±)- was found to exhibit high affinity to S1R and facilitate BDNF release from mouse brain astrocytes. It was also confirmed that compound cannot be oxidized back to the corresponding haloperidol analogue in liver microsomes. Furthermore, compound was distributed to the brain following intraperitoneal administration in mice and reversed the learning deficits in active avoidance tasks. These findings suggest that compound could serve as a promising S1R ligand with therapeutic potential for the treatment of cognitive impairments.
去氢氟哌啶醇（）先前有报道称其作为一种有效的σ-1受体（S1R）配体，与氟哌啶醇相比，对多巴胺D2受体（D2R）的亲和力显著更低。还发现它能以σ-1受体（S1R）依赖的方式促进星形胶质细胞系分泌脑源性神经营养因子（BDNF）。尽管BDNF分泌增加在某些神经疾病中可能具有有益作用，但去氢氟哌啶醇（）的治疗效用有限，因为它在体内可被氧化回氟哌啶醇，而氟哌啶醇是一种强效多巴胺D2受体拮抗剂，具有诸多已被充分记录的不良反应。为尽量减少氧化反应，合成了去氢氟哌啶醇的二氟代类似物，即（±）-4-（4-氯苯基）-1-（3,3-二氟-4-（4-氟苯基）-4-羟基丁基）哌啶-4-醇（）。发现化合物（±）-对S1R具有高亲和力，并能促进小鼠脑星形胶质细胞释放BDNF。还证实化合物在肝微粒体中不会被氧化回相应的氟哌啶醇类似物。此外，在小鼠腹腔注射化合物后，它能分布到脑中，并逆转主动回避任务中的学习缺陷。这些发现表明化合物可作为一种有前景的S1R配体，具有治疗认知障碍的潜力。
