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ID: ALA4765335
Journal: Eur J Med Chem
Title: Privileged scaffold-based design to identify a novel drug-like 5-HT receptor-preferring agonist to target Fragile X syndrome.
Authors: Lacivita E,Niso M,Stama ML,Arzuaga A,Altamura C,Costa L,Desaphy JF,Ragozzino ME,Ciranna L,Leopoldo M
Abstract: Recent preclinical studies have shown that activation of the serotonin 5-HT 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 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 and 5-HT receptors, and screened for their in vitro stability to microsomal degradation and toxicity. Selected compounds were characterized as 5-HT receptor-preferring ligands, endowed with high metabolic stability and low toxicity. Compound 7g emerged as a drug-like 5-HT receptor-preferring agonist capable to rescue synaptic plasticity and attenuate stereotyped behavior in a mouse model of Fragile X syndrome.
CiteXplore: 32442850