Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes

Project: Research project

Description

Treating autism spectrum disorders (ASDs) poses several significant challenges that
remain unmet. In part, this deficiency is a consequence of diverse, multi-component
etiologies. Despite the complexity of these disorders, ASDs do encompass several welldefined
clinical phenotypes including social interaction deficits, impairment in language
and communication, and abnormal repetitive behavior. Current pharmaceutical treatment
of ASD is limited to antipsychotics, selective serotonin uptake inhibitors, such as
fluoxetine, and stimulants, such as methylphenidate. While antipsychotics can reduce
irritability, impulsivity, and overt motor stereotypy, and stimulants can increase focus and
decrease impulsivity, there are currently no approved drugs for treating the profound
social deficits and behavioral inflexibility associated with ASD. The identification of
treatment strategies for core symptoms in ASD will have a major impact on intervention
in neurodevelopmental disorders. Our studies will make the first critical steps towards
new therapeutic approaches for ASD by targeting the oxytocin receptor. Oxytocin is a
nonapeptide hormone that regulates social behavior in addition to its better known
functions in parturition and milk letdown. Previous reports show that oxytocin has
positive effects on ASD test subjects. However, oxytocin itself is a poor drug candidate
because it is a peptide with a short serum half-life and lacks oral bioavailability. In
addition, peripheral effects of oxytocin and its cross-reactivity with vasopressin are likely
to increase chances of side-effects. We therefore initiated a small-molecule oxytocin
receptor agonist and positive allosteric modulator discovery program. Positive allosteric
modulators work to increase the activity of the receptor only in the presence of the
endogenous ligand and therefore are expected to produce fewer side effects. We have
conducted a high throughput screen and identified several unique agonists and positive
allosteric modulators of the human oxytocin receptor. Additionally, we have developed
several mouse models of ASD-like behavioral phenotypes. These tools place our
research team in a unique position to test the hypothesis that activation of central
oxytocin pathways will ameliorate social deficits, repetitive behavior, and other clinical
indices of the ASDs. There are several short term impacts of the successful completion
of our studies. First, we will demonstrate that oxytocin, oxytocin receptor agonists, and
positive allosteric modulators can positively affect social interaction and repetitive
behavior in mouse models with a variety of genetic backgrounds. Results from these first
assays will support the validity of the oxytocin receptor as a small-molecule drug target
and set the stage for significant preclinical studies towards the realization of an oxytocin
receptor activator for ASD treatment. In the long-term, the work will provide leads for a
drug discovery campaign directed at the human oxytocin receptor and provide unique
chemical tools to study the role of the oxytocin pathway in complex social behaviors.
Additionally, the data gathered during the proposed studies will provide us with the
preliminary results necessary to compete successfully for NIH funding.
StatusFinished
Effective start/end date8/8/118/7/15

Funding

  • DOD DA Army Medical Research and Material Command

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Oxytocin Receptors
Autistic Disorder
Phenotype
Oxytocin
Impulsive Behavior
Social Behavior
Interpersonal Relations
Pharmaceutical Preparations
Antipsychotic Agents
Autism Spectrum Disorder
Methylphenidate
Serotonin Uptake Inhibitors
Vasopressins
Biological Availability
Half-Life
Milk
Communication
Parturition
Hormones