Synthesis and Pharmacological Characterization of a Difluorinated Analogue of Reduced Haloperidol as a Sigma-1 Receptor Ligand

Run Duo Gao, Michelle Taylor, Tamara McInnis, Zhenglan Chen, Sadakatali S. Gori, Heather M. LaPorte, Maxime A. Siegler, Janet L. Neisewander, Robert H. Mach, Meharvan Singh, Barbara S. Slusher, Rana Rais, Robert R. Luedtke, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Reduced haloperidol (1) 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 (1) 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 (2), was synthesized in an attempt to minimize the oxidation. Compound (±)-2 was found to exhibit high affinity to S1R and facilitate BDNF release from mouse brain astrocytes. It was also confirmed that compound 2 cannot be oxidized back to the corresponding haloperidol analogue in liver microsomes. Furthermore, compound 2 was distributed to the brain following intraperitoneal administration in mice and reversed the learning deficits in active avoidance tasks. These findings suggest that compound 2 could serve as a promising S1R ligand with therapeutic potential for the treatment of cognitive impairments.

Original languageEnglish (US)
Pages (from-to)947-957
Number of pages11
JournalACS chemical neuroscience
Issue number5
StatePublished - Mar 1 2023


  • active avoidance task
  • brain-derived neurotrophic factor (BDNF)
  • drug metabolism
  • fluorinated molecules
  • reduced haloperidol
  • sigma-1 receptor

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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