Small Molecule Modulators of the Circadian Molecular Clock With Implications for Neuropsychiatric Diseases

Abstract

Circadian rhythms regulate many biological processes and play fundamental roles in behavior, physiology, and metabolism. Such periodicity is critical for homeostasis because disruption or misalignment of the intrinsic rhythms is associated with the onset and progression of various human diseases and often directly leads to pathological states. Since the first identification of mammalian circadian clock genes, numerous genetic and biochemical studies have revealed the molecular basis of these cell-autonomous and self-sustainable rhythms. Specifically, these rhythms are generated by two interlocking transcription/translation feedback loops of clock proteins. As our understanding of these underlying mechanisms and their functional outputs has expanded, strategies have emerged to pharmacologically control the circadian molecular clock. Small molecules that target the molecular clock may present novel therapeutic strategies to treat chronic circadian rhythm-related diseases. These pharmaceutical approaches may include the development of new drugs to treat circadian clock-related disorders or combinational use with existing therapeutic strategies to improve efficacy via intrinsic clock-dependent mechanisms. Importantly, circadian rhythm disruptions correlate with, and often precede, many symptoms of various neuropsychiatric disorders such as sleep disorders, affective disorders, addiction-related disorders, and neurodegeneration. In this mini-review, we focus on recent discoveries of small molecules that pharmacologically modulate the core components of the circadian clock and their potential as preventive and/or therapeutic strategies for circadian clock-related neuropsychiatric diseases.

Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice

“…NOB is among a growing list of small molecules that were identified to directly target the circadian machinery [64,65,66,67,68]. A subset of these clock modifiers have been applied to disease models, and the results have shown promising effects to correct pathophysiological processes related to dysregulated clocks [69,70,71,72,73].…”

SR9009 has REV-ERB–independent effects on cell proliferation and metabolism

“…The importance of proper clock maintenance is highlighted by linkages between circadian desynchrony and a variety of illnesses, including sleep and metabolic disorders, cardiovascular diseases, and cancer (1,2,(4)(5)(6)(7). This has fueled recent interest in the circadian clock as a therapeutic target (8)(9)(10)(11)(12). The nuclear receptors (NRs) REV-ERBα and -β, encoded by Nr1d1 and Nr1d2, link circadian rhythms and metabolism (1,13).…”

Molecular regulation of brain metabolism underlying circadian epilepsy

“…Finally, novel small molecules have been identified that can modulate the circadian molecular system and are currently being investigated in the context of various neurological diseases 127,128 . Some of these small molecules had effects on circadian period, either lengthening or shortening, whereas others modulated circadian phase by delaying it, advancing it, or enhancing its amplitude 129,130 .…”

“…Others had a more direct effects on the circadian molecular system through interacting with and regulating the negative limbs of the system. Agonists and inverse agonists of RORs and REV‐ERBs as well as activators and inhibitors of CRYs have been identified 127,128 . None of these small molecules have been extensively investigated in the context of epilepsy.…”