An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models.
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-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of ()-5-(2-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (()-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki 5.8 nM, EC50 34 nM) and 5-HT1A (Ki 22 nM, EC50 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of ()-5-FPT to reduce stereotypy idiopathic jumping in C58J mice, repetitive body rotations in C57BL6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL6J mice treated with the 5-HT2 agonist, DOI. Systemic ()-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 ()-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.