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. Author manuscript; available in PMC: 2019 Jan 6.
Published in final edited form as: Annu Rev Pharmacol Toxicol. 2017 Oct 2;58:231–252. doi: 10.1146/annurev-pharmtox-010617-052645

Table 2.

Representative small-molecule modulators with other or unknown targetsa

Small molecules Target activity Circadian phenotype Physiological effects References
Opsinamides Melanopsin
 inhibitors		 Suppress light input to
 the SCN		 Generally suppress nonvisual
 photoresponse		 81
SB432542 ALK5 inhibitor Attenuate phase delay Inhibit TGF-β signaling 82
AICAR, metformin AMPK activator Lengthen period
Reduce amplitude		 AICAR: exercise mimetic
Metformin: antidiabetic		 43, 168
CKI-7, IC261, D4476,
 PF-670462, longdaysin,
 LH846, Compound 1-3, and others		 CK1 inhibitor Lengthen period CK1 is broadly involved in
 various pathophysiologies,
 including familial sleep
 and mood disorders		 75, 78
PF-4800567 Selective CK1 ε
 inhibitor		 Blocks PER2
 degradation but shows
 minimal effects on
 circadian period		 Increases sensitivity to
 psychostimulants and opioids		 73
DRB, DMAT CK2 inhibitor Lengthen period Antineoplasia 78, 169
Lithium GSK3 β inhibitor Lengthen period
Enhance amplitude		 Mood disorders 125, 170
Chir99021,
 1-azakenpaullone,
 indirubin		 GSK3 β inhibitor Shorten period Improve glucose metabolism,
 anti-inflammatory and
 antiangiogenesis		 62
L-Methyl selenocysteine Enhance Bmal1
 transcription		 Induction of BMAL1
 protein level and
 activity		 Improved survival of
 cyclophosphamide-sensitive
 Clock mutant mice		 69
Resveratrol Sirt1 activator Modulate physiological
 rhythms and clock gene
 expression		 Broad physiological and
 antiaging efficacies		 140
SRT2183, SRT1720,
 SRTCD1023,
 SRTCL1015		 Sirt1 activator Reduce circadian
 expression
Lengthen period
Reduce amplitude		 Improve circadian clock gene
 expression
Reduce inflammation in
 chronic obstructive pulmonary
 disease		 143, 171
OPC-21268, SSR 149415 Antagonists for
 arginine vasopressin
 receptors
 V1a and V1b, respectively		 Accelerate entrainment
 to jet lag		 Accelerate reentrainment after
 jet lag and shift work		 109
Compound 5, a
 benzodiazepine
 derivative		 GABA receptor
 agonist
Acts on an unknown
 target		 Lengthens period in
 both SCN and
 peripheral clocks		 NA 66
Compound 10/CEM3 Unknown Enhance amplitude and
 shorten period in both
 SCN and peripheral
 clocks		 NA 61,66

Abbreviations: AMPK, AMP-activated protein kinase; CEM, clock-enhancing small molecule; CK1, casein kinase 1; CK2, casein kinase 2; GABA, γ-aminobutyric acid; GSK3 β, glycogen synthase kinase 3 β; NA, not applicable; PER, period; SCN, suprachiasmatic nucleus; TGF-β, transforming growth factor-β.

a

For additional related compounds and references, please refer to a recent review (78).