|
|
CC12CCC3C(C1CCC2=O)CC=C4C3(CCC(C4)O)C |
Approved |
Recent reports, however, have shown that high doses of DHEA (e.g., 100 μM) lengthen circadian period and decrease amplitude
|
NMDA receptor
|
modulation of nuclear receptor signaling pathways
|
Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724.
,
Rey, G., Valekunja, U.K., Feeney, K.A., Wulund, L., Milev, N.B., Stangherlin, A., Ansel-Bollepalli, L., Velagapudi, V., O’Neill, J.S. and Reddy, A.B., 2016. The pentose phosphate pathway regulates the circadian clock. Cell metabolism, 24(3), pp.462-473.
,
Putker, M., Crosby, P., Feeney, K.A., Hoyle, N.P., Costa, A.S., Gaude, E., Frezza, C. and O'Neill, J.S., 2018. Mammalian circadian period, but not phase and amplitude, is robust against redox and metabolic perturbations. Antioxidants & Redox Signaling, 28(7), pp.507-520.
,
Tamai, T. K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M., Nishiwaki-Ohkawa, T., Sato, A., & Yoshimura, T. (2018). Identification of circadian clock modulators from existing drugs. EMBO Molecular Medicine, 10(5), e8724.
|
|
|
CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C |
Approved |
Circadian modulation in human U2OS cells
|
CLOCK-BMAL1
,
Arntl (gene)
,
BMAL1 expression (induction)
|
Bmal1,
de-repressing BMAL1,
BMAL1 expression modulation,
BMAL1 expression modulation,
Retinoic acid receptor RXR-alpha, beta, gamma binding,
Binding retinoic acid receptor alpha
|
Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724.
|
|
|
CC1=C(C=C(C=C1)NC2=NC=CC(=N2)N(C)C3=CC4=NN(C(=C4C=C3)C)C)S(=O)(=O)N.Cl |
Approved |
Circadian modulation in human U2OS cells
|
CLOCK-BMAL1
,
Arntl (gene)
,
BMAL1 expression (induction)
|
Bmal1,
de-repressing BMAL1,
BMAL1 expression modulation,
BMAL1 expression modulation,
Vascular endothelial growth factor receptor 1, 2, 3,
Platelet-derived growth factor receptor alpha, beta,
Mast/stem cell growth factor receptor Kit,
Fibroblast growth factor receptor 3,
Tyrosine-protein kinase ITK/TSK,
Fibroblast growth factor 1,
SH2B adapter protein 3
|
Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724.
|
|
|
C1=CC=C(C=C1)S(=O)(=O)N(CC(F)(F)F)C2=CC=C(C=C2)C(C(F)(F)F)(C(F)(F)F)O |
Not approved |
Circadian modulation via nuclear receptor pathways (LXRα/β) in mammalian cells
|
Liver X receptors
|
LXRα,
LXRβ
|
Ribeiro, R.F., Cavadas, C. and Silva, M.M.C., 2021. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), pp.1620-1641.
,
Gbaguidi, G.F. and Agellon, L.B., 2004. The inhibition of the human cholesterol 7α‐hydroxylase gene (CYP7A1) promoter by fibrates in cultured cells is mediated via the liver x receptor α and peroxisome proliferator‐activated receptor α heterodimer. Nucleic acids research, 32(3), pp.1113-1121.
,
Feillet, C., Guérin, S., Lonchampt, M., Dacquet, C., Gustafsson, J.Å., Delaunay, F. and Teboul, M., 2016. Sexual Dimorphism in Circadian Physiology Is Altered in LXR α Deficient Mice. PLoS One, 11(3), p.e0150665.
,
Ribeiro, R. F. N., Cavadas, C., & Silva, M. M. C. (2021). Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), 1620–1641.
|
|
|
CN1C2=C(C(=O)N(C1=O)C)NC=N2.CN1C2=C(C(=O)N(C1=O)C)NC=N2.C(CN)N |
Approved |
Period lengthening in fungi
|
Adenosine A1, A2A, A2B, and A3 Receptors
|
cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A Inhibitor,
Adenosine receptor A1Antagonist,
cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A,
Adenosine receptor A3Antagonist
|
Olivares-Yañez, C., Alessandri, M.P., Salas, L. and Larrondo, L.F., 2023. Methylxanthines modulate circadian period length independently of the action of phosphodiesterase. Microbiology Spectrum, 11(4), pp.e03727-22.
,
Manrui, L., Xu, Y., Liu, J., Zhang, X., Yuan, R., Sun, Y., Sun, Y., Yang, Q., Liao, M., Lv, M. and Hu, X., 2025. Aminophylline targets miR-128-3p/Slc7a11 axis to attenuate neuronal ferroptosis after traumatic brain injury. Cellular and Molecular Life Sciences, 82(1), pp.1-23.
|
|
|
CC1=C(C=C(C=C1)C(=O)NC2=CC(=CC(=C2)C(F)(F)F)N3C=C(N=C3)C)NC4=NC=CC(=N4)C5=CN=CC=C5 |
Approved |
Circadian gene expression modulation in human cells (U2OS)
|
CLOCK-BMAL1
,
Arntl (gene)
,
BMAL1 expression (induction)
,
Tyrosine proteine kinase ABL1
|
Bmal1,
de-repressing BMAL1,
BMAL1 expression modulation,
BMAL1 expression modulation,
"Tyrosine-protein kinase ABL1 Mast/stem cell growth factor receptor binding
|
Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724.
|
|
|
CC(=O)NCCC1=C(NC2=CC=CC=C21)CC3=CC=CC=C3 |
not approved |
Phase shift disruption in animals
|
Melatonin receptor
|
Melatonin receptor binding,
antagonist of melatonin receptors
|
Dubocovich, M.L., 1988. Luzindole (N-0774): a novel melatonin receptor antagonist. Journal of Pharmacology and Experimental Therapeutics, 246(3), pp.902–910.
,
Estarás, M., Ameur, F.Z., Roncero, V., Fernández-Bermejo, M., Blanco, G., López, D., Mateos, J.M., Salido, G.M. and González, A., 2019. The melatonin receptor antagonist luzindole induces Ca²⁺ mobilization, reactive oxygen species generation and impairs trypsin secretion in mouse pancreatic acinar cells. Biochimica et Biophysica Acta (BBA) - General Subjects, 1863(11), p.129407.
|
|
|
CCCCCCC(C)(C)C1=CC(=C2C3CC(=O)CCC3C(OC2=C1)(C)C)O |
Approved |
Sleep improvement; potential indirect circadian stabilization via CB1 activation
|
Cannabinoid receptor
|
Cannabinoid receptor stimulation
|
Peball, M., Heim, B., Carbone, F., Schorr, O., Werkmann, M., Ellmerer, P., Marini, K., Krismer, F., Knaus, H.G., Poewe, W., Djamshidian, A. and Seppi, K., 2024. Long-term safety and efficacy of open-label nabilone on sleep and pain in Parkinson’s disease. NPJ Parkinson’s Disease, 10(1), p.61.
|
|
|
CCC(=O)NCCC1CCC2=C1C3=C(C=C2)OCC3 |
Approved |
Phase advance in humans,
5-h phase advance in the sleep-wake cycle
|
Melatonin receptor
|
Melatonin receptor binding
|
Richardson, G.S., Zee, P.C., Wang-Weigand, S., Rodriguez, L. and Peng, X., 2008. Circadian phase-shifting effects of repeated ramelteon administration in healthy adults. Journal of Clinical Sleep Medicine, 4(5), pp.456–461.
,
Takeshima, M., Shimizu, T., Ishikawa, H. and Kanbayashi, T., 2020. Ramelteon for delayed sleep-wake phase disorder: a case report. Clinical Psychopharmacology and Neuroscience, 18(1), pp.167–169.
,
Zammit, G.K., 2007. Ramelteon: a novel hypnotic indicated for the treatment of insomnia. Psychiatry (Edgmont), 4(9), pp.36–42.
|
|
|
CC(=O)N1CCCC(C1)C2=CNC3=C2C=C(C=C3)OC |
Not approved |
Circadian disruption via melatonin receptor antagonism
|
Melatonin receptor
|
Melatonin receptor antagonist
|
Teh, M.T. and Sugden, D., 1999. The putative melatonin receptor antagonist GR128107 is a partial agonist on Xenopus laevis melanophores. British Journal of Pharmacology, 126(5), pp.1237–1245.
,
Teh, M.T. and Sugden, D., 1999. The putative melatonin receptor antagonist GR128107 is a partial agonist on Xenopus laevis melanophores. British Journal of Pharmacology, 126(5), pp.1237–1245.
|
|
|
CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC |
Approved |
restores normal circadian rhythms
|
T58921 Peroxisome proliferator-activated receptor gamma (PPAR-gamma)
,
Melatonin receptor
,
MT3
,
MT1
,
MT2
,
RORα
,
Mel1C
,
CAND2
,
VDR
,
QR2
,
MMP9
,
PEPSIN
,
PP2A
,
mPTP
,
PEPT1
,
PEPT2
,
GLUT1
,
HBS
,
CaM
,
TUBULIN
,
Calreticulin
|
SIRT1,
Melatonin receptor binding,
ROR,
RORγ binding,
RORyt/RORc inhibitor,
Melatonin receptor agonist,
Antioxidant
|
Arendt, J. and Skene, D.J., 2005. Melatonin as a chronobiotic. Sleep Medicine Reviews, 9(1), pp.25–39.
,
Pévet, P., Bothorel, B., Slotten, H. and Saboureau, M., 2002. The chronobiotic properties of melatonin. Cell and Tissue Research, 309, pp.183–191.
,
Cardinali, D.P., 2024. Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved. Journal of Pineal Research, 76(1), p.e12931.
|
|
|
C1=CC(=CC=C1/C=C/C2=CC(=CC(=C2)O)O)O |
Approved |
Resveratrol can influence the expression of key clock genes like CLOCK, BMAL1, PER, and CRY, which are involved in establishing and maintaining the 24
|
T60529
,
MTOR (Human)
,
CLOCK-BMAL1 COMPLEX
|
SIRT1,
mTOR signaling inhibition,
Serine/threonine-protein kinase mTOR,
Altering Circadian Metabolism via the SIRT1-AMPK-PP2A Axis,
Repression of PER/CRY feedback loops via deacetylation.,
AMPK-PP2A axis suppresses mTOR, advancing circadian phase in muscle.
|
Sun, L., Wang, Y., Song, Y., Cheng, X.R., Xia, S., Rahman, M.R., Shi, Y. and Le, G., 2015. Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice. Biochemical and Biophysical Research Communications, 458(1), pp.86–91.
,
Spaleniak, W. and Cuendet, M., 2023. Resveratrol as a circadian clock modulator: mechanisms of action and therapeutic applications. Molecular Biology Reports, 50, pp.6159–6170.
,
Avital-Cohen, N., Chapnik, N. and Froy, O., 2024. Resveratrol induces myotube development by altering circadian metabolism via the SIRT1-AMPK-PP2A axis. Cells, 13, p.1069.
|
|
|
CC(=O)NCC1CC2=CC=CC=C2CC3=C1C=C(C=C3)OC |
not approved |
Phase shift disruption in mammals
|
Melatonin receptor
|
antagonist of melatonin receptors
|
Spadoni, G., Bedini, A., Diamantini, G., Tarzia, G., Rivara, S., Lorenzi, S., Lodola, A., Mor, M., Lucini, V., Pannacci, M., Caronno, A. and Fraschini, F., 2007. Synthesis, enantiomeric resolution, and structure–activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists. ChemMedChem, 2(12), pp.1741–1749.
,
Lucini, V., Pannacci, M., Scaglione, F., Fraschini, F., Rivara, S., Mor, M., Bordi, F., Plazzi, P.V., Spadoni, G., Bedini, A., Piersanti, G., Diamantini, G. and Tarzia, G., 2004. Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity. Journal of Medicinal Chemistry, 47(17), pp.4202–4212.
|
|
|
CC(NC([2H])([2H])C([2H])([2H])C1=CNC2=C1C=C(OC)C=C2)=O |
Approved |
Phase shift induction in mammals via MT1/MT2 receptor agonism
|
MT1
,
MT2
|
Melatonin receptor binding
|
González, S., Moreno-Delgado, D., Moreno, E., Pérez-Capote, K., Franco, R., Mallol, J., Cortés, A., Casadó, V., Lluís, C., Ortiz, J., Ferré, S., Canela, E. and McCormick, P.J., 2012. Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biology, 10(6), p.e1001347.
|
|
|
CC(=O)NCCC1=C(NC2=C1C=C(C=C2)OC)I |
not approved |
Phase shift induction in mammals via MT1/MT2 receptor agonism
|
MT1
,
MT2
|
SIRT1,
Melatonin receptor binding,
MT2 receptor antagonist,
MT1 receptor binding
|
Masana, M.I., Benloucif, S. and Dubocovich, M.L., 2000. Circadian rhythm of MT1 melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse. Journal of Pineal Research, 28(3), pp.185–192.
,
Larson-Prior, L.J., Siuciak, J.A. and Dubocovich, M.L., 1996. Localization of 2-[¹²⁵I]iodomelatonin binding sites in visual areas of the turtle brain. European Journal of Pharmacology, 297(1–2), pp.181–185.
|
|
|
CCC(=O)NC1CCC2=C(C1)C(=CC=C2)OC |
Not approved |
Phase shift modulation in mammals via selective MT2 receptor agonism
|
MT2
|
MT2 receptor ligand
|
Mendoza-Vargas, L., Solís-Chagoyán, H., Benítez-King, G. and Fuentes-Pardo, B., 2009. MT2-like melatonin receptor modulates amplitude receptor potential in visual cells of crayfish during a 24-hour cycle. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 154(4), pp.486–492.
,
Ambriz-Tututi, M. and Granados-Soto, V., 2007. Oral and spinal melatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors. Pain, 132(3), pp.273–280.
|
|
|
CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC |
Aapproved |
Phase shift in humans via MT1/MT2 receptor agonism,
Agomelatine has been shown to induce robust circadian phase shifts,
can improve sleep continuity and quality, shorten sleep latency (time it takes to fall asleep,
advance the timing of sleep onset and other circadian rhythms like core body temperature and heart rate.
|
Melatonin receptor
|
antagonist of melatonin receptors
|
Pandi-Perumal, S.R., Moscovitch, A., Srinivasan, V., Spence, D.W., Cardinali, D.P. and Brown, G.M., 2009. Bidirectional communication between sleep and circadian rhythms and its implications for depression: lessons from agomelatine. Progress in Neurobiology, 88(4), pp.264–271.
,
Tchekalarova, J., Stoynova, T., Ilieva, K., Mitreva, R. and Atanasova, M., 2018. Agomelatine treatment corrects symptoms of depression and anxiety by restoring the disrupted melatonin circadian rhythms of rats exposed to chronic constant light. Pharmacology Biochemistry and Behavior, 171, pp.1–9.
,
Souza, L.C., Martynhak, B.J., Bassani, T.B., Turnes, J.D.M., Machado, M.M., Moura, E., Andreatini, R. and Vital, M.A., 2018. Agomelatine's effect on circadian locomotor rhythm alteration and depressive-like behavior in 6-OHDA lesioned rats. Physiology & Behavior, 188, pp.298-310.
|
|
|
CC(NCCN1C2=CC(OC)=C(Cl)C=C2N=C1OC)=O |
not approved |
Circadian rhythm entrainment in diet-induced obese rats via MT1/MT2 agonism
|
Melatonin receptor
,
MT1
,
MT2
|
MT1 receptor binding,
MT2 receptor ligand
|
Ferreira, M.A. Jr, Azevedo, H., Mascarello, A., Segretti, N.D., Russo, E., Russo, V. and Guimarães, C.R.W., 2021. Discovery of ACH-000143: a novel potent and peripherally preferred melatonin receptor agonist that reduces liver triglycerides and steatosis in diet-induced obese rats. Journal of Medicinal Chemistry, 64(4), pp.1904–1929.
|
|
|
CC(=O)NCCC1=C(NC2=C1C=C(C=C2)OC)C3=CC=CC=C3 |
not approved |
MT1/MT2 receptor agonist; potential circadian phase modulation in mammals
|
Melatonin receptor
,
MT1
,
MT2
|
MT1 receptor binding,
MT2 receptor ligand,
Melatonin agonist
|
Radogna, F., Paternoster, L., De Nicola, M., Cerella, C., Ammendola, S., Bedini, A., Tarzia, G., Aquilano, K., Ciriolo, M. and Ghibelli, L., 2009. Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes. Toxicology and Applied Pharmacology, 239(1), pp.37–45.
,
Mor, M., Spadoni, G., Di Giacomo, B., Diamantini, G., Bedini, A., Tarzia, G., Plazzi, P.V., Rivara, S., Nonno, R., Lucini, V., Pannacci, M., Fraschini, F. and Stankov, B.M., 2001. Synthesis, pharmacological characterization and QSAR studies on 2-substituted indole melatonin receptor ligands. Bioorganic & Medicinal Chemistry, 9(4), pp.1045–1057.
|
|
|
CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC.Cl |
approved |
restores normal circadian rhythms,
Resynchronization of the circadian clock, potentially improving sleep quality and alleviating symptoms associated with sleep disturbances.
|
Melatonin receptor
|
Melatonin receptor binding
|
Tchekalarova, J., Stoynova, T., Ilieva, K., Mitreva, R. and Atanasova, M., 2018. Agomelatine treatment corrects symptoms of depression and anxiety by restoring the disrupted melatonin circadian rhythms of rats exposed to chronic constant light. Pharmacology Biochemistry and Behavior, 171, pp.1–9.
,
Mairesse, J., Silletti, V., Laloux, C., Zuena, A.R., Giovine, A., Consolazione, M., van Camp, G., Malagodi, M., Gaetani, S., Cianci, S., Catalani, A., Mennuni, G., Mazzetta, A., van Reeth, O., Gabriel, C., Mocaër, E., Nicoletti, F., Morley-Fletcher, S. and Maccari, S., 2013. Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats. International Journal of Neuropsychopharmacology, 16
|
|
|
CC(=O)NCCC1=CNC2=CC=CC=C21 |
Not approved |
Partial MT2 receptor agonist; modulates circadian signaling in retina (mammals)
|
Melatonin receptor
,
MT1
|
Melatonin receptor binding,
MT1 receptor binding
|
Backlund, P.S., Urbanski, H.F., Doll, M.A., Hein, D.W., Bozinoski, M., Mason, C.E., Coon, S.L. and Klein, D.C., 2017. Daily rhythm in plasma N-acetyltryptamine. Journal of Biological Rhythms, 32(3), pp.195–211.
,
Pohanka, M., 2022. New uses of melatonin as a drug: a review. Current Medicinal Chemistry, 29(20), pp.3622–3637.
|
|
|
CC(=O)NCCC1=C2C=C(C=CC2=CC(=C1)O)O |
None |
Weak MT1/MT2 agonist
|
MT1
,
MT2
|
Melatonin receptor binding,
MT1 receptor binding,
MT2 receptor ligand
|
Bogaards, J.J., Hissink, E.M., Briggs, M., Weaver, R., Jochemsen, R., Jackson, P., Bertrand, M. and van Bladeren, P.J., 2000. Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling. European Journal of Pharmaceutical Sciences, 12(2), pp.117–124.
|
|
|
[2H]C([2H])(C1=CC=CC2=C1C=C(C=C2)OC)C([2H])([2H])NC(=O)C |
Not approved |
derivative of chronobiotic agomelatine (MT1/MT2)
|
Melatonin receptor
|
Melatonin receptor binding
|
De Berardis, D., Marini, S., Fornaro, M., Srinivasan, V., Iasevoli, F., Tomasetti, C., Valchera, A., Perna, G., Quera-Salva, M.A., Martinotti, G. and Di Giannantonio, M., 2013. The melatonergic system in mood and anxiety disorders and the role of agomelatine: implications for clinical practice. International Journal of Molecular Sciences, 14(6), pp.12458–12483.
|
|
|
[2H]C([2H])([2H])C(NC([2H])([2H])C([2H])([2H])C(C1=C2)=CNC1=CC=C2OC)=O |
not approved |
MT1/MT2 receptor agonist
|
MT1
,
MT2
|
Melatonin receptor binding,
MT1 receptor binding,
MT2 receptor ligand
|
Fourtillan, J.B., Brisson, A.M., Gobin, P., Ingrand, I., Decourt, J.P. and Girault, J., 2000. Bioavailability of melatonin in humans after day-time administration of D(7) melatonin. Biopharmaceutics & Drug Disposition, 21(1), pp.15–22.
|
|
|
[2H]C([2H])([2H])C([2H])([2H])C(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3 |
Approved |
MT1/MT2 receptor agonist
|
Melatonin receptor
|
Melatonin receptor binding
|
McGechan, A. and Wellington, K., 2005. Ramelteon. CNS Drugs, 19(12), pp.1057–1065; discussion 1066–1067.
|