Central Modulation of Circadian Rhythm via CK1 Inhibition for Psychiatric Indications

Publisher Summary This chapter discusses the central modulation of circadian rhythms (CRs) via casein kinase (CK1) inhibition for psychiatric indications. Circadian biology involves the study of CRs, which are periodic behavioral and physiologic processes that cycle approximately every 24 h. CRs are primarily regulated by an organism's environmental photoperiod (day/night); thus, CRs likely function to synchronize critical biologic processes with light/dark cycles. CRs in higher organisms are generated by a master clock located in the suprachiasmatic nucleus of the brain. The master clock synchronizes central and peripheral clocks in the body regulating numerous and diverse functions including sleep–wake cycles, hormone release, and body temperature. There is a growing body of evidence linking disrupted CRs to the pathophysiology of neuropsychiatric diseases, including insomnia, depression, seasonal affective disorder, and bipolar disorder. Mammalian genetics has played a large part in defining the components of the circadian timing system. In humans, familial advanced sleep phase syndrome is a disease in which patients show a daily advance in the time when they go to sleep. Confirmation of CK1 as a drug-able target is validated by the identification of chemical matter consistent with drug-like attributes, including good ligand efficiency, lipophilic efficiency, and brain availability. Moreover, these compounds have provided the in vivo translation of circadian biology and have shown CR entrainment and phase shifts in nonhuman primates and rodents.