An Orally Active Phenylaminotetralin-Chemotype Serotonin 5‑HT₇ and 5‑HT_1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models

Abstract

Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT₇ receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT_1A partial agonist with relevant affinity at 5-HT₇ receptors. Herein, we report the synthesis, <i>in vitro</i> molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2′-fluorophenyl)-<i>N</i>,<i>N</i>-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT₇ (<i>K</i>_i = 5.8 nM, EC₅₀ = 34 nM) and 5-HT_1A (<i>K</i>_i = 22 nM, EC₅₀ = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (<i>+</i>)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT₂ agonist, DOI. Systemic (<i>+</i>)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (<i>+</i>)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders