|
|
CC(=CCC1=CC(=C(C=C1O)O)C(=O)/C=C/C2=CC=C(C=C2)O)C |
none |
Amplitude enhancement in human cells
|
RORA
,
RORα
|
ROR
|
Dang, Y., Ling, S., Ma, J., Ni, R. and Xu, J.W., 2015. Bavachalcone enhances RORα expression, controls Bmal1 circadian transcription, and depresses cellular senescence in human endothelial cells. Evidence‐based Complementary and Alternative Medicine, 2015(1), p.920431.
|
|
|
C1=CC(=CC=C1C2=NC(=C(N2)C3=CC=NC=C3)C4=CC=C(C=C4)F)O |
Not approved |
Period lengthening in Aplysia.
|
p38 MAP kinase
|
Inhibits p38 MAPK α/β isoforms
|
Hirota, T., Lewis, W.G., Liu, A.C., Lee, J.W., Schultz, P.G. and Kay, S.A., 2008. A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3β. Proceedings of the National Academy of Sciences, 105(52), pp.20746-20751.
,
Shanware, N.P., Williams, L.M., Bowler, M.J. and Tibbetts, R.S., 2009. Non-specific in vivo inhibition of CK1 by the pyridinyl imidazole p38 inhibitors SB 203580 and SB 202190. BMB reports, 42(3), p.142.
,
Sankrithi, N. and Eskin, A., 1999. Effects of Cyclin‐Dependent Kinase Inhibitors on Transcription and Ocular Circadian Rhythm of Aplysia. Journal of neurochemistry, 72(2), pp.605-613.
|
|
|
CCC(=O)NC1CC(C2=CC=CC=C2C1)C3=CC=CC=C3 |
not approved |
blocks melatonin-induced phase shifts
|
Melatonin receptor
|
antagonist of melatonin receptors
|
Liu, W., Chen, Z., Li, R., Zheng, M., Pang, X., Wen, A., Yang, B. and Wang, S., 2023. High and low dose of luzindole or 4-phenyl-2-propionamidotetralin (4-P-PDOT) reverse bovine granulosa cell response to melatonin. PeerJ, 11, p.e14612.
|
|
|
CC1=CC(=C(C=C1)C(C2=CC=CC=C2)NC(=O)CC3=CC4=C(C=C3)OC(=C4)C(C5=C(ON=C5C)C)O)C |
Not approved |
Modulation of circadian gene expression via RORγt inhibition in mice/human immune cells
|
RORα
|
ROR
|
Lyu, C., Bing, S.J., Wandu, W.S., Xu, B., Shi, G., Hinshaw, S.J., Lobera, M., Caspi, R.R., Lu, L., Yang, J. and Gery, I., 2018. TMP778, a selective inhibitor of RORγt, suppresses experimental autoimmune uveitis development, but affects both Th17 and Th1 cell populations. European journal of immunology, 48(11), pp.1810-1816.
,
Venken, K., Jacques, P., Mortier, C., Labadia, M.E., Decruy, T., Coudenys, J., Hoyt, K., Wayne, A.L., Hughes, R., Turner, M. and Van Gassen, S., 2019. RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients. Nature communications, 10(1), p.9.
|
|
|
C1=CC(=C(C=C1/C=C/C(=O)O[C@@H](C(=O)O)[C@@H](OC(=O)/C=C/C2=CC(=C(C=C2)O)O)C(=O)O)O)O |
none |
restores normal circadian rhythms
|
PGC-1α
,
CLOCK-BMAL1
,
GSK-3α/β
|
PGC-1α interaction,
Core clock modulation,
Activation of CLOCK/Bmal1 mediated transcription,
Interferes with CLOCK–BMAL1,
Selective GSK-3β Inhibition:,
Circadian Clock Impact,
inhibits glycogen synthase kinase-3β (GSK-3β)
|
Guo, R., Zhao, B., Wang, Y., Wu, D., Wang, Y., Yu, Y., Yan, Y., Zhang, W., Liu, Z. and Liu, X., 2018. Cichoric acid prevents free-fatty-acid-induced lipid metabolism disorders via regulating Bmal1 in HepG2 cells. Journal of agricultural and food chemistry, 66(37), pp.9667-9678.
|
|
|
CC1=C(C=CC(=C1)S(=O)(=O)N2CCCCC2)OC |
Not approved |
Inhibition of light-induced phase shifts via melanopsin antagonism
|
Melanopsin (Opn4)
|
Competitive blockade of melanopsin’s retinal-binding site
|
Obayashi, K., Zou, R., Kawaguchi, T., Mori, T. and Tsukamoto, H., 2025. Molecular basis underlying the specificity of an antagonist AA92593 for mammalian melanopsins. Journal of Biological Chemistry, 301(5), p.108461.
,
Bertolesi, G.E., Debnath, N., Malik, H.R., Man, L.L. and McFarlane, S., 2022. Type II opsins in the eye, the pineal complex and the skin of Xenopus laevis: Using changes in skin pigmentation as a readout of visual and circadian activity. Frontiers in Neuroanatomy, 15, p.784478.
|
|
|
CC(=O)NCCC1=CNC2=C1C=C(C=C2)NC(=O)OC |
not approved |
Melatonin receptor agonism
|
MT3
|
MT3 receptor ligand
|
Pintor, J., Peláez, T., Hoyle, C.H. and Peral, A., 2003. Ocular hypotensive effects of melatonin receptor agonists in the rabbit: further evidence for an MT3 receptor. British Journal of Pharmacology, 138(5), pp.831–836.
,
Crooke, A., Huete-Toral, F., Martínez-Águila, A., Martín-Gil, A. and Pintor, J., 2012. Involvement of carbonic anhydrases in the ocular hypotensive effect of melatonin analogue 5-MCA-NAT. Journal of Pineal Research, 52(3), pp.265–270.
|
|
|
CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)OCCO)C)C)O)OC)C)C)C)OC |
Approved |
Circadian modulation in human cells
|
CLOCK-BMAL1
,
BMAL1 expression (induction)
|
Bmal1,
de-repressing BMAL1,
BMAL1 expression modulation,
BMAL1 expression modulation,
mTOR signaling inhibition,
Serine/threonine-protein kinase mTOR
|
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=CC=CC2=C1N=C(CN3C[C@H]4C[C@@H](C3)C5=CC=CC(=O)N5C4)N=C2NC6=CC=C7C(=C6)OCO7 |
none |
Lengthen perion of circadian rhythm
|
CRY1
,
CRY2
|
Selective stabilizer of CRY1,
Selectively stabilizes CRY2,
CRY 2 Stabilizer
|
Surme, S., Ergun, C., Gul, S., Akyel, Y.K., Gul, Z.M., Ozcan, O., Ipek, O.S., Akarlar, B.A., Ozlu, N., Taskin, A.C. and Turkay, M., 2023. TW68, cryptochromes stabilizer, regulates fasting blood glucose levels in diabetic ob/ob and high fat-diet-induced obese mice. Biochemical Pharmacology, 218, p.115896.
|
|
|
C1CCN(CC1)CCOC2=CC=C(C=C2)C(=O)C3=C(SC4=C3C=CC(=C4)O)C5=CC=C(C=C5)O |
None |
Period shortening of the circadian rhythm in the uterus
|
PER2 gene expression
|
BMAL1 expression modulation
|
Nakamura TJ, Sellix MT, Menaker M, Block GD. Estrogen directly modulates circadian rhythms of PER2 expression in the uterus. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1025-31. doi: 10.1152/ajpendo.90392.2008. Epub 2008 Aug 26. PMID: 18728223; PMCID: PMC2584820.
|
|
|
CCC(=O)NCC1CC1C2=C3CCOC3=CC=C2 |
Approved |
Circadian phase entrainment via MT1/MT2 receptor agonism
|
Melatonin receptor
,
MT1
,
MT2
|
Melatonin receptor binding,
MT1 receptor binding,
MT2 receptor ligand
|
Nishimon, S., Nishimon, M. and Nishino, S., 2019. Tasimelteon for treating non-24-h sleep–wake rhythm disorder. Expert Opinion on Pharmacotherapy, 20(9), pp.1065–1073.
,
Torres, R., Kramer, W.G. and Baroldi, P., 2015. Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment. Journal of Clinical Pharmacology, 55(5), pp.525–533.
|
|
|
C1=CC=C(C(=C1)C2=NN(C(=N2)C3=CC=CC=C3O)C4=CC=C(C=C4)C(=O)O)O |
Approved |
Period lengthening in human U2OS cells
|
CLOCK-BMAL1
,
BMAL1 expression (induction)
,
Fe
|
Bmal1,
BMAL1 expression modulation,
BMAL1 expression modulation
|
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=CC=CC2=C1C=C(C=C2)OCCCOC3=CC4=C(C=CC=C4CCNC(=O)C)C=C3 |
not approved |
Phase shift disruption in mammals via MT1/MT2 receptor antagonism
|
Melatonin receptor
,
MT1
,
MT2
|
Melatonin receptor binding,
MT2 receptor antagonist,
MT1 receptor binding
|
Descamps-François, C., Yous, S., Chavatte, P., Audinot, V., Bonnaud, A., Boutin, J.A., Delagrange, P., Bennejean, C., Renard, P. and Lesieur, D., 2003. Design and synthesis of naphthalenic dimers as selective MT1 melatoninergic ligands. Journal of Medicinal Chemistry, 46(7), pp.1127–1129.
,
Audinot, V., Mailliet, F., Lahaye-Brasseur, C., Bonnaud, A., Le Gall, A., Amossé, C., Dromaint, S., Rodriguez, M., Nagel, N., Galizzi, J.P., Malpaux, B., Guillaumet, G., Lesieur, D., Lefoulon, F., Renard, P., Delagrange, P. and Boutin, J.A., 2003. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn–Schmiedeberg’s Archives of Pharmacology, 367(6), pp.553–561.
|
|
|
CCNC(=O)CC[C@@H](C(=O)O)N |
none |
l-Theanine significantly enhanced the expression of BMAL1, a clock gene in melanoma cells.
|
BMAL1 expression (induction)
|
de-repressing BMAL1,
BMAL1 expression modulation,
BMAL1 expression modulation
|
Zhang, R., Liu, M., Lu, J., Lu, S., Wang, Y. and Guan, S., 2024. Fisetin Ameliorates Hepatocyte Lipid Droplet Accumulation via Targeting the Rhythmic Protein BMAL1 to Regulate Cell Death-Inducing DNA Fragmentation Factor-α-like Effector C-Mediated Lipid Droplet Fusion. Journal of Agricultural and Food Chemistry, 72(48), pp.26884-26897.
|
|
|
CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=CC(=NC(=N3)C)N4CCN(CC4)CCO |
Approved |
Period lengthening in human U2OS cells
|
CLOCK-BMAL1
,
BMAL1 expression (induction)
|
Bmal1,
BMAL1 expression modulation,
BMAL1 expression modulation,
"Tyrosine-protein kinase ABL1, Lck, Yes, Fyn, BTK, CSK, Fgr, FRK, Lyn Proto-oncogene tyrosine-protein kinase Src Ephrin type-A
|
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.
|
|
|
COC1=CC2=C(C=C1)NC=C2CCNC(=O)C3=CC(=O)C=CO3 |
Not approved |
Circadian rhythm synchronization via melatonin receptor agonism
|
Melatonin receptor
,
MT3
,
MT1
,
MT2
|
MT3 receptor ligand,
MT1 receptor binding,
MT2 receptor ligand
|
Tchekalarova, J., Kortenska, L., Marinov, P. and Ivanova, N., 2022. Sex-dependent effects of piromelatine treatment on sleep–wake cycle and sleep structure of prenatally stressed rats. International Journal of Molecular Sciences, 23(18), p.10349.
,
She, M., Hu, X., Su, Z., Zhang, C., Yang, S., Ding, L., Laudon, M. and Yin, W., 2014. Piromelatine, a novel melatonin receptor agonist, stabilizes metabolic profiles and ameliorates insulin resistance in chronic sleep restricted rats. European Journal of Pharmacology, 727, pp.60–65.
|
|
|
CC(C(=O)NCCC1CCC2=C1C3=C(C=C2)OCC3)O |
Not approved |
improves sleep (cats)
|
Melatonin receptor
,
MT1
,
MT2
|
Melatonin receptor binding,
MT1 receptor binding,
MT2 receptor ligand
|
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.
,
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.
|
|
|
CC(C)C(CCCN(C)CCC1=CC(=C(C=C1)OC)OC)(C#N)C2=CC(=C(C=C2)OC)OC |
Approved |
Shortening of circadian period
|
CLOCK-BMAL1
|
BMAL1 expression modulation
|
Burish MJ, Han C, Mawatari K, Wirianto M, Kim E, Ono K, Parakramaweera R, Chen Z, Yoo SH. The first-line cluster headache medication verapamil alters the circadian period and elicits sex-specific sleep changes in mice. Chronobiol Int. 2021 Jun;38(6):839-850. doi: 10.1080/07420528.2021.1892127. Epub 2021 Apr 8. PMID: 33829951.
|
|
|
C1=CC(=C(C=C1/C=C/C2=CC(=CC(=C2)O)O)O)O |
Not approved |
Piceatannol advanced PER2::LUC luminescence rhythm in peripheral organs in vivo.,
recovered phase change of PER2::LUC disturbed by high-fat diet intake.,
affects Per2 expression and may prevent circadian disturbance.
|
Per2 expression
,
Per 1 expression (gene)
|
PER gene exspression modulation
|
Yamamoto, T., Iwami, S., Aoyama, S., Maruki-Uchida, H., Mori, S., Hirooka, R., Takahashi, K., Morita, M. and Shibata, S., 2019. Effect of piceatannol on circadian Per2 expression in vitro and in vivo. Journal of functional foods, 56, pp.49-56.
|
|
|
CC(C)(C)C(=O)OCOP(=O)(COCCN1C=NC2=C(N=CN=C21)N)OCOC(=O)C(C)(C)C |
Approved |
|
CLOCK-BMAL1
,
Arntl (gene)
,
BMAL1 expression (induction)
|
Bmal1,
de-repressing BMAL1,
BMAL1 expression modulation,
BMAL1 expression modulation,
DNA polymerase/reverse transcriptase (HBV-D) 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.
|
|
|
[2H]C([2H])([2H])C(=O)NCCC1=CNC2=C1C=C(C=C2)OC |
Approved |
|
MT1
|
Melatonin receptor binding
|
Rajaratnam, S.M., Middleton, B., Stone, B.M., Arendt, J. and Dijk, D.J., 2004. Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans. Journal of Physiology, 561(1), pp.339–351.
|
|
|
CC(C(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3)O |
Approved |
MT1/MT2 partial agonist
|
Melatonin receptor
|
Melatonin agonist
|
ChatGPT сказал: Nishiyama, K., Nishikawa, H., Kato, K., Miyamoto, M., Tsukamoto, T. and Hirai, K., 2014. Pharmacological characterization of M-II, the major human metabolite of ramelteon. Pharmacology, 93(3–4), pp.197–201.
|
|
|
CN(C)CCC=C1C2=CC=CC=C2CCC3=CC=CC=C31 |
approved |
sleep architecture modulation
|
CLOCK-BMAL1
|
BMAL1 expression modulation
|
Silva S, Bicker J, Falcão A, Fortuna A. Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression. Pharmaceutics. 2021 Nov 21;13(11):1975. doi: 10.3390/pharmaceutics13111975.
|
|
|
CCCC(=O)NCCC1=C2C=C(C=CC2=CN=N1)OC |
Not approved |
|
MT1
,
MT2
|
Melatonin receptor binding
|
Dubocovich, M.L., 2007. Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Medicine, 8(Suppl 3), pp.34–42.
|
|
|
C1=CC=C2C(=C1)C=CN2 |
not approved |
Phase-shift
|
Melatonin receptor
|
Melatonin receptor binding
|
Axelrod, J., 1983. Regulation of circadian rhythms of indoleamines in the pineal gland. In The pineal gland and its endocrine role (pp. 1-13). Boston, MA: Springer US.
|