Circadian regulation of behavioral, metabolic, and endocrine function is a fundamental homeostatic process. Disruption of the circadian clock has been linked to sleep and psychiatric disorders at the genetic and molecular level. We initiated a discovery program in Phase I to identify ligands to a previously unexplored orphan receptor that directly interacts with the core circadian clock transcriptional loop. The receptor is expressed predominantly in the CNS and is especially prominent in the suprachiasmatic nucleus (SCN), the hypothalamic region that provides master control of circadian function. The receptor has a role in the circadian cycle and in affective disorders based on the phenotype of the knockout mouse. A centrally-acting small molecule that is capable of shifting the phase of the SCN, or entraining and consolidating signals from the SCN, will have widespread therapeutic potential in circadian rhythm sleep disorders (CRSDs) such as delayed sleep phase disorder (DSPD), jet lag, shift work sleep disorder, and dementia, where disruption of sleep-wake patterns is of major economic and clinical significance. Melatonin and its analogues, which have soporific as well as circadian phase-shifting effects, are not widely used in these indications, primarily due to lack of efficacy. Light is beneficial as chronotherapy but presents practical problems with administration. There is considerable potential for a more efficacious chronotherapeutic. With Phase I support we developed the first screening assays, discovered hits, and identified a lead-like ligand that has good potency (EC50 200 nM), plasma stability (terminal half-life = 1 hour) and blood-brain barrier penetration (brain:plasma ratio = 1). Agonists and antagonists directly regulate the promoter of BMAL1, a core clock component, as predicted by molecular studies. We propose in Aim 1 to carry out final optimization of a lead for in vivo studies and to investigate pharmacological regulation of circadian cycling in isolated SCN to model potential in vivo effects.
In Aim 2, we characterize circadian phase shifting by short-term exposure to ligand in mice free running on a 24 h period in the dark, a classic test of a potential chronotherapeutic. Based on these early findings, we test phase shifting protocols that might point to clinical utility, such as constant entrainment with respect to light for a sleep phase disorder, or acceleration of entrainment following a 6 h shift in the light-dark cycle resembling jet lag.
In Aim 3, an optimized lead will be tested by chronic dosing in models of anxiety, depression, and psychosis. Current therapies for sleep and psychiatric disorders are inconsistent in their effectiveness. The project described herein offers the first opportunity to develop chronotherapeutic drugs to a novel target that has emerged from fundamental investigations of the circadian clock molecular mechanisms.
Sleep disorders and mental illness affect up to 60 million Americans on an annual basis. The cost for treatment is $205 billion/year, accounting for 15% of annual U.S. healthcare costs. At the same time, current drugs are therapeutically inadequate for many patients and are based on small number of drug targets. The molecular components of the transcriptional clock that keeps the body's circadian time have been only recently recognized as having widespread involvement in sleep-wake disorders as well as dementia and perhaps mood and psychiatric disorders. Modulation of this transcriptional network could have a major impact in the area of CNS therapeutics.
