Development of Novel Drugs Targeting Serotonin Receptors to Treat Motor, Social, Cognitive, and Sensory Domains of Autism Spectrum Disorder Using Mouse Models
Background: There is a critical medical need for pharmacotherapy to treat symptoms associated with autism spectrum disorder (ASD). ASD affects nearly 1% of the population, and there is no approved pharmacotherapy for the core symptoms of autism; the antipsychotic medications risperidone and aripiprazole are approved to treat irritability only. Synthesis of a corpus of scientific literature, involving both clinical and preclinical data, provided the foundation for a robust rationale to develop serotonin (5HT) 5HT1A/5HT7 agonists to treat core ASD symptoms. Noteworthy is that in early 2016 buspirone, a 5HT1A partial agonist without 5HT7 activity, was reported as effective to ameliorate restricted and repetitive behaviors (only) in children with ASD. Our initial medicinal chemistry/molecular pharmacology efforts have led to the discovery of a novel, dual 5HT1A/5HT7 receptor partial agonist, a 5-phenyl-2-aminotetralin (5-PAT), 5-FPT. In vivo, 5-FPT corrects repetitive behaviors caused by glutamate NMDA receptor dysfunction and enhances social behavior in wild-type mouse models. These preliminary data supply the thrust to pursue this line of research in Shank3 mutant mice addressing the Fiscal Year 2016 Autism Research Program Idea Development Award Area of Interest, "Assessment of novel therapeutics using valid preclinical models."Objective: The primary objective is to synthesize novel 5-PATs with optimal 5HT1A to 5HT7 pharmacology and to test their efficacy to correct deficits in a Shank3 mutant mouse model of ASD. Successful completion will facilitate the goal to advance an ASD medication candidate to Investigational New Drug (IND)-enabling studies for clinical development. In addition, this work will (1) quantify expression of NMDA, GABAA, 5HT1A, and 5HT7 receptors in Shank3 mutant (and wild-type) mice in neural systems where Shank3 expression is normally enriched; (2) quantify plasma oxytocin in Shank3 (and wild-type) mice; and (3) determine whether these putative biomarkers, which we hypothesize will be decreased in Shank3 mutants, are modulated by 5-PATs.Specific Aims and Study Design: Aim 1: Synthesize novel 5-PAT 5HT1A and 5HT7A agonists. A homology, structure-based approach will be used for 5HT1A and 5HT7 agonist development. We propose synthesis of 70 additional analogs to probe SAR of both receptors in order to have in-hand one selective 5HT1A, one selective 5HT7, and one dual agonist, iteratively, based on results of Aim 2. Aim 2: Assess molecular pharmacology of 5-PATs at target and off-target GPCRs. All analogs will be screened for affinity (Ki) at human and mouse recombinant 5HT1A and 5HT7 receptors using radioreceptor assay technology well-established in our lab. Ligands with 5HT1A and/or 5HT7 affinity
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
