Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5‑HT₃ and 5‑HT₆ Receptor Antagonist with Antipsychotic and Procognitive Properties

In
line with recent
clinical trials demonstrating that ondansetron,
a 5-HT3 receptor (5-HT3R) antagonist, ameliorates
cognitive deficits of schizophrenia and the known procognitive effects
of 5-HT6 receptor (5-HT6R) antagonists, we applied
the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and
a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration.
Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity
and displays procognitive properties in the novel object recognition
task. In contrast to FPPQ, neither 5-HT6R
inverse agonist SB399885 nor neutral 5-HT6R antagonist
CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified
by FPPQ, contributes to alleviating the positive-like
symptoms. Present findings reveal critical structural features useful
in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting
5-HT3/5-HT6R antagonists for the treatment of
psychiatric disorders.