DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

The Development of Novel Drugs to Treat the Core Symptoms of ASD

Posted April 23, 2020

Raymond Booth, Ph.D., Northeastern University
Clinton Canal, Ph.D., Mercer University

Dr. Ray Booth
Dr. Ray Booth

Dr. Clinton Canal
Dr. Clinton Canal

Currently, there is no approved pharmacotherapy for the core debilitating symptoms of Autism Spectrum Disorder (ASD), which are impaired social interactions, communication difficulties, and repetitive behaviors. The option of pharmacologic interventions could be monumental for many individuals with ASD, allowing them to function better and improve their quality of life. The complexity of ASD has made the development of pharmacotherapy for ASD challenging. A number of factors, including genetic, infectious, immunologic, metabolic, nutritional, and toxic factors are thought to be involved. Moreover, different brain areas, neuronal connections, neuronal receptors, and neuronal proteins may be affected.

Evidence suggests that imbalances in the ratio of excitatory to inhibitory neurons contribute to the core symptoms of ASD. Serotonin (5-HT) is a chemical that helps stabilize a person’s mood and has been linked to ASD. Blood 5-HT levels have been shown to correlate with repetitive behaviors and diet-induced reduction of 5-HT increases these behaviors. Thus, the 5-HT receptors are poised as viable targets for ASD pharmacotherapy. There are 14 distinct 5-HT receptors. The 5-HT1A and 5-HT7 receptors, in particular, are expressed in regions of the brain that control behaviors altered in ASD, and there is preclinical evidence that partial agonists to each receptor improves ASD symptoms. Drs. Raymond Booth and Clinton Canal postulated that targeting both receptors together may realize greater success.

The Autism Research Program (ARP) awarded Drs. Booth and Canal a fiscal year 2016 Idea Development Award to explore the development of novel drugs targeting serotonin receptors to treat ASD using mouse models. The team set out to design and synthesize compounds that target the 5-HT1A and 5-HT7 serotonin receptors, yielding varying degrees of receptor activity. The team had previously identified a compound that partially activates 5-HT7 and 5-HT1A receptors; with ARP support they next investigated structural modifications of the lead compound that might impact 5-HT7 and 5-HT1A selectivity and improve the effectiveness of the compound. The team uncovered three new 5-HT1A and 5-HT7 receptor compounds with unique functional pharmacology and varying degrees of efficacy at 5-HT1A and 5-HT7. The three new compounds attenuate repetitive behaviors in normal mice. One lead compound, 5-fluorophenyl-2-aminotetralin (FPT), modulated several behaviors in a genetic mouse model of ASD, including increasing social interactions, decreasing repetitive and anxiety-like behaviors, and preventing seizures caused by auditory stimuli. Furthermore, after FPT administration, c-Fos expression selectively increased in the amygdala of the autism mouse model, which might be a neural signal of reduced anxiety.

These results demonstrate that the team has identified a compound that targets serotonin receptors and yields receptor activity that corrects the ASD core symptoms of repetitive behavior and impaired social interactions. The team will continue testing their lead compound as well as other top candidates in mouse models of ASD. They are on track to obtain an Investigational New Drug Application, a request for authorization from the Food and Drug Administration to administer an investigational drug to humans. New pharmacotherapy options addressing core symptoms of ASD are in urgent need. Drs. Booth and Canal’s research provides hope to the autism community that new medicines for relieving autism’s most disabling symptoms are on the horizon.

Publications:

Armstrong JL, Casey AB, Saraf TS, Mukherjee M, Booth RG, Canal CE. 2020. (S)-5-(2′-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder. ACS Pharmacol Transl Sci. doi.org/10.1021/acsptsci.9b00101. Epub ahead of print.

Perry CK, Casey AB, Felsing DE, Vemula R, Zaka M, Herrington NB, Cui M, Kellogg GE, Canal CE, Booth RG. 2020. Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling. Bioorg Med Chem. 28(3):115262.

Felsing DE, Canal CE, and Booth RG. 2019. Ligand-directed serotonin 5-HT2C receptor desensitization and sensitization. Eur J Pharmaco. 848:131–139.

Link:

Public and Technical Abstracts: Development of Novel Drugs Targeting Serotonin Receptors to Treat Motor, Social, Cognitive, and Sensory Domains of Autism Spectrum Disorder Using Mouse Models

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Last updated Tuesday, August 18, 2020