Translation of Novel Serotonin 5-HT7 Agonist Drug Candidates in Rodent Models of Fragile X Syndrome
Abstract
This Discovery Award research proposal addresses the topic of Fragile X Syndrome (FXS). FXS is the most common monogenetic form of intellectual disability, and there are no drugs approved to treat core symptoms of FXS, which include deficits in cognitive functioning, speech and language, and social and emotional control, stereotypical movements, sensory overload, and increased seizure susceptibility. FXS is caused by mutation of the fragile X mental retardation 1 gene (FMR1) that leads to elimination of the FMR1 protein, FMRP. Lack of FMRP is hypothesized to lead to aberrant overexpression of proteins regulated by certain glutamatergic neurotransmitter receptors, disrupting normal brain development and causing FXS symptoms. Support for this "glutamatergic theory" of FXS pathogenesis emanated from observations that genetic knockdown of specific glutamatergic neurotransmitter receptors corrected FXS symptoms in the Fmr1-knockout (KO) mouse model of FXS, an animal model that recapitulates many key human FXS behavioral, cognitive, and physiological symptoms. Thus, small molecule drug discovery strategies have focused on glutamatergic receptor antagonists that have been shown to correct FXS behavioral, structural, and physiological symptoms in the Fmr1-KO mouse. A recent Phase IIb/III clinical trial of the glutamatergic receptor antagonist AFQ056 (mavoglurant) for FXS, however, did not succeed in meeting desired therapeutic endpoints, and concerns exist about the psychoactive and neurotoxic effects of glutamatergic receptor antagonists. The serotonin (5-hydroxytryptamine, 5HT) neurotransmitter system is also critically altered in FXS, and recently it was observed that activation of the serotonin 5HT7 receptor produces effects similar to glutamatergic receptor antagonists in Fmr1-KO mice. 5HT7 receptors indirectly modulate glutamate receptor activity and are highly expressed in neural systems that contribute to FXS symptoms, e.g., sensory hypersensitivity and intellectual impairments. These observations provide the thrust of this application: to test the innovative hypothesis that 5HT7 receptor agonist drugs could safely and effectively treat FXS symptoms in mouse models that recapitulate human FXS. This hypothesis fosters new directions for FXS pharmacotherapy, and unpublished, preliminary data disclosed for the first time in the current application indicate that novel 5-phenyl-2-dimethylaminotetralin (5-PAT)-type 5HT7 agonists, proposed to be further developed herein, correct stereotyped movements in FXS mouse models, similar to glutamatergic receptor antagonists, though notably, with greater efficacy. Objective and Specific Aims: The objective here is to synthesize potent and efficacious 5-PAT-type 5HT7 receptor agonists and assess their effectiveness to correct FXS symptoms in Fmr1-KO mice and other mouse models of FXS symptoms. This objective will be achieve by completing the following three specific aims: Aim 1, design and syntheses of novel 5-PAT-type 5HT7 ligands, will focus on structural modification that optimizes 5-PAT binding interactions with the 5HT7 receptor, as suggested from molecular modeling studies. A total of 46 novel 5-PAT analogs are proposed for synthesis. Aim 2, 5-PAT affinity and functional pharmacology at 5HT7 in comparison to related neurotransmitter receptors will be delineated using clonal cells expressing human recombinant 5HT7 receptors in comparison to related receptors. Lead compounds with high human 5HT7 selectivity, potency, and efficacy will be tested at mouse receptors, and pharmacological activity criteria will help guide selection of 5-PATs predicted to translate in vivo regarding efficacy in Fmr1 KO mice and mouse models of FXS symptoms in Aim 3 translational studies. Aim 3, translation of 5-PATs in a variety of mouse models of FXS, including use of Fmr1 KO mice, C58/J mice that display excessive stereotypic jumping, and 5HT7 knockout mice to validate 5HT7 receptor depend
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510247
Entities
People
- Raymond G. Booth
Organizations
- Northeastern University
- United States Army