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

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.