RT Journal Article
T1 Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder
A1 Lacivita, Enza
A1 Niso, Mauro
A1 Mastromarino, Margherita
A1 García Silva, Andrea
A1 Resch, Cibell
A1 Zeug, Andre
A1 Loza García, María Isabel
A1 Castro Pérez, María de los Ángeles
A1 Ponimaskin, Evgeni
A1 Leopoldo, Marcello
K1 5-HT7 receptor
K1 5-HT1A receptor
K1 5-HT2A receptor
K1 Arylpiperazine
K1 Autism spectrum disorder
K1 Knowledge-based design
AB Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders characterized by core symptomssuch as impaired social interaction and communication, repetitive and stereotyped behaviors, and restricted interests. To date, thereare no effective treatments for these core symptoms. Several studies have shown that the brain serotonin (5-HT) neurotransmissionsystem is altered in both ASD patients and animal models of the disease. Multiple pieces of evidence suggest that targeting 5-HTreceptors may treat the core symptoms of ASD and associated intellectual disabilities. In fact, stimulation of the 5-HT1A receptorreduces repetitive and restricted behaviors; blockade of the 5-HT2A receptor reduces both learning deficits and repetitive behavior,and activation of the 5-HT7 receptor improves cognitive performances and reduces repetitive behavior. On such a basis, we havedesigned novel arylpiperazine derivatives pursuing unprecedently reported activity profiles: dual 5-HT7/5-HT1A receptor agonistproperties and mixed 5-HT7 agonist/5-HT1A agonist/5-HT2A antagonist properties. Seventeen new compounds were synthesizedand tested in radioligand binding assay at the target receptors. We have identified the dual 5-HT1AR/5-HT7R agonists 8c and 29 andthe mixed 5-HT1AR agonist/5-HT7R agonist/5-HT2AR antagonist 20b. These compounds are metabolically stable in vitro and havesuitable central nervous system druglike properties.
PB American Chemical Society
YR 2021
FD 2021
LK http://hdl.handle.net/10347/32834
UL http://hdl.handle.net/10347/32834
LA eng
NO Lacivita E, Niso M, Mastromarino M, Andrea, Silva A, Resch C, Zeug A, Loza MI, Castro M, Ponimaskin E, and Leopoldo M. knowledge-based design of long-chain arylpiperazine derivatives targeting multiple serotonin receptors as potential candidates for treatment of autism spectrum disorder. ACS Chem. Neurosci. 2021, 12, 1313−1327. https://doi.org/10.1021/acschemneuro.0c00647
NO The present work was partially supported by Telethon Foundation Grant GGP13145 (M.L.) and by German Research Foundation (DFG) (grant number PO732 to E.P. and grantnumber ZE994/2 to A.Z.). A.G.S., M.I.L., and M.C. acknowledge support from the Spanish Ministry of Economy and Competitiveness (MINECO) (grant number SAF2014-57138-C2−1-R), Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019−2022, grant number ED431G 2019/02), and the European Union (European Regional DevelopmentFund - ERDF). COST Action CA 18133 “EuropeanResearch Network on Signal Transduction − ERNEST” isgratefully acknowledged. Funding for open access charge:COST Action CA18133 (ERNEST)
DS Minerva
RD 24 abr 2026