Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome.

Recent preclinical studies have shown that activation of the serotonin 5-HT7 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-HT7 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-HT7 and 5-HT1A receptors, and screened for their in vitro stability to microsomal degradation and toxicity. Selected compounds were characterized as 5-HT7 receptor-preferring ligands, endowed with high metabolic stability and low toxicity. Compound 7g emerged as a drug-like 5-HT7 receptor-preferring agonist capable to rescue synaptic plasticity and attenuate stereotyped behavior in a mouse model of Fragile X syndrome. Copyright © 2020. Published by Elsevier Masson SAS.

Citation

Enza Lacivita, Mauro Niso, Madia Letizia Stama, Anna Arzuaga, Concetta Altamura, Lara Costa, Jean-François Desaphy, Michael E Ragozzino, Lucia Ciranna, Marcello Leopoldo. Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome. European journal of medicinal chemistry. 2020 Aug 01;199:112395

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PMID: 32442850

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