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

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

  • Eur J Med Chem. 2020 Aug 1:199:112395. doi: 10.1016/j.ejmech.2020.112395.
Enza Lacivita 1,  Mauro Niso 1,  Madia Letizia Stama 1,  Anna Arzuaga 2,  Concetta Altamura 3,  Lara Costa 4,  Jean-François Desaphy 3,  Michael E Ragozzino 5,  Lucia Ciranna 6,  Marcello Leopoldo 7
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona 4, 70125, Bari, Italy.
  • 2 Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
  • 3 Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari Aldo Moro, Policlinico, piazza Giulio Cesare, 70126, Bari, Italy.
  • 4 Dipartimento di Medicina Clinica e Sperimentale, Università di Messina, Via Consolare Valeria 1, Messina, Italy.
  • 5 Department of Psychology, University of Illinois at Chicago, Chicago, IL, 60607, USA.
  • 6 Dipartimento di Scienze Biomediche e Biotecnologiche, Università di Catania, Via Santa Sofia 97, Catania, Italy.
  • 7 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona 4, 70125, Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.
PMID: 32442850 DOI: 10.1016/j.ejmech.2020.112395
Abstract

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.

Keywords

5-HT(7) receptor; Arylpiperazine; Fragile X syndrome; Pharmacokinetic properties; Privileged scaffold-based design.

Figures