Privileged scaffold-based design to identify a novel drug-like 5-HT 7 receptor-preferring agonist to target Fragile X syndrome.

Recent preclinical studies have shown that activation of the serotonin 5-HT ₇ receptor has the potential to treat neurodevelopmental disorders such as Fragile X syndrome, a rare disease characterized by autistic features. With the aim to provide the scientific community with diversified drug-like 5-HT ₇ receptor-preferring agonists, we designed a set of new long-chain arylpiperazines by exploiting structural fragments present in clinically approved drugs or in preclinical candidates (privileged scaffolds). The new compounds were synthesized, tested for their affinity at 5-HT ₇ and 5-HT _1A receptors, and screened for their in vitro stability to microsomal degradation and toxicity. Selected compounds were characterized as 5-HT ₇ receptor-preferring ligands, endowed with high metabolic stability and low toxicity. Compound 7g emerged as a drug-like 5-HT ₇ receptor-preferring agonist capable to rescue synaptic plasticity and attenuate stereotyped behavior in a mouse model of Fragile X syndrome.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020. Published by Elsevier Masson SAS.)