Dysregulation of the circadian rhythm is associated with several disorders of the nervous system including anxiety disorders. Anxiety disorders are a serious medical illness affecting approximately 40 million adults in the United States. Benzodiazepenes are the most commonly utilized anxiolytic drugs, but their use is associated with significant side effects including sedation, tolerance and potential for abuse. There are a number of anxiolytic drugs that are now available, but these also are less than optimal. Thus, there is a clear unmet medical need for additional classes of therapeutics to treat these disorders. This proposed research is based on our recent discovery that we can modulate the circadian rhythm in vivo with synthetic ligands for a particular nuclear receptor (NR), REV-ERB. REV-ERBalpha is an NR that has a well-characterized role in the regulation of the circadian rhythm. We have found that REV-ERB agonists that we have designed that has the ability to modulate the circadian rhythm in vivo also display anxiolytic activity in mice. Interestingly, thes compounds display no sedative activity at anxiolytic doses. The REV-ERB agonists we have developed are the first with sufficient in vivo exposure to allow evaluation of its effects in animals; however, their pharmacodynamic and pharmcokinetic properties are far from optimal. We hypothesize that optimized synthetic REV-ERB ligands will have utility in treatment of anxiety disorders. We will address this hypothesis by focusing on the following specific aims: 1) Optimize the pharmacodynamic and pharmacokinetic properties of synthetic REV-ERB ligands for use as anxiolytic agents, 2) Evaluate the ability of synthetic REV- ERB ligands for their abiliy to modulate circadian behavior/physiology in vivo, 3) Optimize the anxiolytic activity of REV-ERB agonists in vivo and characterize their sedative activity and potential for abuse. We have now developed a series of very potent and efficacious REV-ERB agonists that have properties that will allow for evaluation of these compounds in animal models of disease. Thus, our proposed research is highly innovative and has the potential to have high impact since this work may lead to novel drugs for the treatment of anxiety disorders as well as other behavioral disorders.
We discovered that the nuclear receptor REV-ERB is ligand regulated and have characterized both synthetic agonists and antagonists of this receptor. This receptor is a key regulator of the circadian rhythm and dysregulation of the circadian rhythm is associated with several disorders of the nervous system including anxiety disorders. We have discovered that REV-ERB agonists display anxiolytic activity and the goal of this proposal is to develop REV-ERB agonists with optimized pharmacodynamic and pharmacokinetic properties for use as anxiolytic agents.
|Pourcet, Benoit; Zecchin, Mathilde; Ferri, Lise et al. (2018) Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice. Gastroenterology 154:1449-1464.e20|
|Welch, Ryan D; Billon, Cyrielle; Valfort, Aurore-Cecile et al. (2017) Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle. Sci Rep 7:17142|
|Sitaula, Sadichha; Zhang, Jinsong; Ruiz, Fernanda et al. (2017) Rev-erb regulation of cholesterologenesis. Biochem Pharmacol 131:68-77|
|Girardet, Clemence; Burris, Thomas P; Butler, Andrew A (2015) SIRT1 in the Ventromedial Hypothalamus: A Nutrient Sensor Input Into the Internal Timekeeper. Endocrinology 156:1936-8|
|Guo, Chun; Li, Yali; Gow, Chien-Hung et al. (2015) The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor ? requires G protein pathway suppressor 2. J Biol Chem 290:3666-79|
|Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M et al. (2015) Suppression of atherosclerosis by synthetic REV-ERB agonist. Biochem Biophys Res Commun 460:566-71|
|Butler, Andrew A; Burris, Thomas P (2015) Segregation of Clock and Non-Clock Regulatory Functions of REV-ERB. Cell Metab 22:197-8|
|Wang, Yongjun; Kojetin, Douglas; Burris, Thomas P (2015) Anti-proliferative actions of a synthetic REV-ERB?/? agonist in breast cancer cells. Biochem Pharmacol 96:315-22|
|Matta-Camacho, Edna; Banerjee, Subhashis; Hughes, Travis S et al. (2014) Structure of REV-ERB? ligand-binding domain bound to a porphyrin antagonist. J Biol Chem 289:20054-66|
|Banerjee, Subhashis; Wang, Yongjun; Solt, Laura A et al. (2014) Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat Commun 5:5759|
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