Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders characterized by core symptoms such as impaired social interaction and communication, repetitive and stereotyped behaviors, and restricted interests. To date, there are no effective treatments for these core symptoms. Several studies have shown that the brain serotonin (5-HT) neurotransmission system is altered in both ASD patients and animal models of the disease. Multiple pieces of evidence suggest that targeting 5-HT receptors may treat the core symptoms of ASD and associated intellectual disabilities. In fact, stimulation of the 5-HT_1A receptor reduces repetitive and restricted behaviors; blockade of the 5-HT_2A 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 have designed novel arylpiperazine derivatives pursuing unprecedently reported activity profiles: dual 5-HT₇/5-HT_1A receptor agonist properties and mixed 5-HT₇ agonist/5-HT_1A agonist/5-HT_2A antagonist properties. Seventeen new compounds were synthesized and tested in radioligand binding assay at the target receptors. We have identified the dual 5-HT_1AR/5-HT₇R agonists 8c and 29 and the mixed 5-HT_1AR agonist/5-HT₇R agonist/5-HT_2AR antagonist 20b. These compounds are metabolically stable in vitro and have suitable central nervous system druglike properties.

Keywords: 5-HT1A receptor; 5-HT2A receptor; 5-HT7 receptor; arylpiperazine; autism spectrum disorder; knowledge-based design.