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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (DDNS)
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Driscoll, Jamie
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Scripps Florida
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Kojetin, Douglas J; Burris, Thomas P (2014) REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov 13:197-216
Kojetin, Douglas J; Burris, Thomas P (2013) Small molecule modulation of nuclear receptor conformational dynamics: implications for function and drug discovery. Mol Pharmacol 83:1-8
Woldt, Estelle; Sebti, Yasmine; Solt, Laura A et al. (2013) Rev-erb-* modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat Med 19:1039-46