An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models

Clinton E. Canal, Daniel Felsing, Yue Liu, Wanying Zhu, Jodianne T. Wood, Charles K. Perry, Rajender Vemula, Raymond G. Booth

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1259-1270
Number of pages12
JournalACS Chemical Neuroscience
Volume6
Issue number7
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

Fingerprint

Receptor, Serotonin, 5-HT1A
Serotonin
Rett Syndrome
Fragile X Syndrome
Serotonin 5-HT2 Receptor Agonists
Buspirone
Pharmacokinetics
Inbred C57BL Mouse
Dizocilpine Maleate
Serotonin Receptors
N-Methylaspartate
Amines
Serotonin Syndrome
Pharmacology
Serotonin 5-HT1 Receptor Agonists
Chemical activation
Interpersonal Relations
Autistic Disorder
Synaptic Transmission
Oral Administration

Keywords

  • 5-HT
  • 5-HT
  • autism
  • mice
  • partial agonist
  • receptor
  • Stereotypy

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models. / Canal, Clinton E.; Felsing, Daniel; Liu, Yue; Zhu, Wanying; Wood, Jodianne T.; Perry, Charles K.; Vemula, Rajender; Booth, Raymond G.

In: ACS Chemical Neuroscience, Vol. 6, No. 7, 15.07.2015, p. 1259-1270.

Research output: Contribution to journalArticle

Canal, Clinton E. ; Felsing, Daniel ; Liu, Yue ; Zhu, Wanying ; Wood, Jodianne T. ; Perry, Charles K. ; Vemula, Rajender ; Booth, Raymond G. / An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models. In: ACS Chemical Neuroscience. 2015 ; Vol. 6, No. 7. pp. 1259-1270.
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