Development of Novel Drugs Targeting Serotonin Receptors to Treat Motor, Social, Cognitive, and Sensory Domains of Autism Spectrum Disorder Using Mouse Models
Abstract
This project addresses the Fiscal Year 2016 Autism Research Program Idea Development Award Area of Interest "Assessment of novel therapeutics using valid preclinical models." There is a critical, unmet, medical need for medicines to treat the core symptoms of autism. In 2010, the Centers for Disease Control and Prevention estimated an autism prevalence rate in children of 1.5%, and a new study calculated that the cost of autism (assuming a prevalence rate of 1.1%) will likely surpass diabetes in the next decade, moving autism to one of the top, costliest, medical conditions. Despite these alarming numbers, no medications are approved to treat core symptoms of autism, including repetitive and/or restricted behaviors and difficulties with social interactions. There are two antipsychotic drugs (risperidone and aripiprazole), with myriad of problematic side effects, approved only to treat irritability associated with autism. The main objective of this project is to synthesize new medicines that have a novel mechanism involving the brain chemical serotonin and assess their effectiveness to treat the core symptoms of autism, first, by using laboratory animals. The specific serotonin targets of the new medicines under development are called serotonin 1A and serotonin 7 receptors. Targeting serotonin 1A and 7 receptors represents an innovative approach to treat autism, supported by a strong rationale. Many alterations in the serotonin system are associated with autism. For example, individuals with autism have decreased brain levels of serotonin 1A receptors, and certain autism risk genes are necessary for the development of the brain s serotonin system. Previous approaches at developing medicines for autism that target brain chemicals gamma-aminobutyric acid (GABA) and glutamic acid have failed. Thus, the biomedical scientists involved with the current proposal believe it is time to move to alternative approaches, such as those involving restoring a proper balance of serotonin neurotransmission believed to be altered in patients with autism. In connection with our research to develop medicines for schizophrenia, addiction, and compulsive-impulsive behavioral disorders (such as attention deficit hyperactivity disorder or ADHD), we synthesized dozens of molecules and discovered an innovative, new experimental drug candidate called "5-FPT" that activates both serotonin 1A and serotonin 7 receptors. We observed that 5-FPT enhanced social behaviors and eliminated repetitive behaviors (that were drug induced) in non-autistic laboratory mice. Presumably, 5-FPT provided an optimal balance of serotonin function in these mice. These promising preliminary results warrant further investigation of 5-FPT in genetic mouse models of autism (that provide a more rigorous testing paradigm than wild mice). Furthermore, given that about 90% of drugs fail at some point in the development process, we will need to have several back-up drug candidates -- the pharmaceutical industry standard is four total drug candidates for testing. Accordingly, pharmaceutical synthesis of a variety of candidates molecules (70 total) with chemical structures different but related to 5-FPT will be synthesized and tested -- early screening will help to cull the less active molecules and those with toxicity, prior to testing in mice. This drug discovery and development research is highly likely to lead to a novel medication for autism that treats repetitive behaviors, social deficits, and also cognitive deficits. We already have started to partner with a small biotech pharmaceutical start-up company (Seropeutics) to help move the very expensive drug development project forward, pending funding of our application to synthesize and test the 5-FPT-type drug candidates. In addition, this research will provide 70 new drug-like chemicals that will benefit autism research, as well as, the broader neuroscience/drug development research community, as well as pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710329
Entities
People
- Clinton E Canal
Organizations
- Mercer University
- United States Army