title: An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A 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-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 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 (+)-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.
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Canal
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Felsing
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Wanying
authors.initials: W
authors.lastname: Zhu
authors.forename: JodiAnne T
authors.initials: JT
authors.lastname: Wood
authors.forename: Charles K
authors.initials: CK
authors.lastname: Perry
authors.forename: Rajender
authors.initials: R
authors.lastname: Vemula
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000662:Amphetamines; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C000606746:5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine; D000662:Amphetamines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A; D016291:Dizocilpine Maleate; D015081:2-Naphthylamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
keywords: 5-HT1A; 5-HT7; Stereotypy; autism; mice; partial agonist; receptor