|
|
CC1=[N+](C2=CC=CC=C2C(=C1)N)CCCCCCCCCC[N+]3=C(C=C(C4=CC=CC=C43)N)C.[Cl-].[Cl-] |
Approved |
Modulation of circadian gene expression in human U2OS cells
|
CLOCK-BMAL1
|
Bmal1,
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.
|
|
|
ClC=1C=C(C=CC1Cl)N1C(NC2=C(C1=O)C=NN2C2=CC=CC=C2)=O |
none |
reduces the levels of PRR7 protein in Arabidopsis
|
CCA1
|
PRR
|
Uehara, T.N., Takao, S., Matsuo, H., Saito, A.N., Ota, E., Ono, A., Itami, K., Kinoshita, T., Yamashino, T., Yamaguchi, J. and Nakamichi, N., 2023. A Small-Molecule Modulator Affecting the Clock-Associated PSEUDO-RESPONSE REGULATOR 7 Amount. Plant And Cell Physiology, 64(11), pp.1397-1406.
|
|
|
CN1CCN(CC1)C2=NC3=C(C=CC(=C3)Cl)NC4=CC=CC=C42 |
Approved |
restores normal circadian rhythms
|
5-HT7
|
5-HT7 binding
|
Wirz-Justice, A., Werth, E., Savaskan, E., Knoblauch, V., Gasio, P.F. and Müller-Spahn, F., 2000. Haloperidol disrupts, clozapine reinstates the circadian rest–activity cycle in a patient with early-onset Alzheimer disease. Alzheimer Disease & Associated Disorders, 14(4), pp.212-215.
|
|
|
CC(C1=CC=CC=C1)(C2=CC=CC=N2)OCCN(C)C.C(CC(=O)O)C(=O)O |
Approved |
effects on the circadian rhythm, also known as the body's natural sleep-wake cycle, are primarily related to its drowsiness and sedation properties
|
Histamine 1 receptor
|
Histamine 1 blocker
|
Ward, L.G., Bourjeily, G., Guthrie, K., Salmoirago-Blotcher, E., Sharp, M., Desmarattes, A. and Bublitz, M., 2024. Sleep Quality in High-Risk Pregnancies: Mixed Methods Results from a Randomized Controlled Trial of a Mindfulness Training Intervention. Journal of Integrative and Complementary Medicine, 30(10), pp.953-960.
|
|
|
CC(C)(C)OC(=O)CC1=CC(=C(C=C1CC2=CC(=C(C=C2[125I])OC)OC)OC)OC |
None |
MT2 antagonist; disrupts melatonin signaling (in human receptor models),
Partial agonist MT2 and associated effects
|
MT2
|
MT2 receptor ligand
|
Legros, C., Brasseur, C., Delagrange, P., Ducrot, P., Nosjean, O. and Boutin, J.A., 2016. Alternative radioligands for investigating the molecular pharmacology of melatonin receptors. The Journal of Pharmacology and Experimental Therapeutics, 356(3), pp.681-692.
,
Legros, C., Matthey, U., Grelak, T., Pedragona-Moreau, S., Hassler, W., Yous, S., Thomas, E., Suzenet, F., Folleas, B., Lefoulon, F. and Berthelot, P., 2013. New radioligands for describing the molecular pharmacology of MT1 and MT2 melatonin receptors. International journal of molecular sciences, 14(5), pp.8948-8962.
|
|
|
(B. bifidum W23, B. lactis W51, B. lactis W52) and lactobacilli (L. acidophilus W22, L. casei W56, L. paracasei W20, L. plantarum W62, L. salivarius W24, L. lactis W19) |
Not approved |
restores normal circadian rhythms
|
CLOCK-BMAL1
,
Arntl (gene)
,
NPAS2
,
BMAL1 expression (induction)
,
TIMELESS
|
Core clock modulation,
Bmal1,
Activation of CLOCK/Bmal1 mediated transcription,
Circadian Clock Impact,
TIMELESS
|
Kreuzer, K., Birkl-Toeglhofer, A.M., Haybaeck, J., Reiter, A., Dalkner, N., Fellendorf, F.T., Maget, A., Platzer, M., Seidl, M., Mendel, L.M. and Lenger, M., 2024. PROVIT-CLOCK: A Potential Influence of Probiotics and Vitamin B7 Add-On Treatment and Metabolites on Clock Gene Expression in Major Depression. Neuropsychobiology, 83(3-4), pp.135-151.
|
|
|
C1CN(CCC1(C2=CC=C(C=C2)Cl)O)CCCC(=O)C3=CC=C(C=C3)F |
Approved |
affect expression of PER1 and CRY1 genes in human glioblastoma cell line
|
mPer1
,
CRY1-PER2 complex
,
CRY1
,
CRY1
|
PER gene exspression modulation,
CRY gene expression modulation
|
Mokros, Ł., Karbownik, M.S., Nowakowska-Domagała, K., Szemraj, J., Wieteska, Ł., Woźniak, K., Witusik, A., Antczak, A. and Pietras, T., 2016. Haloperidol, but not olanzapine, may affect expression of PER1 and CRY1 genes in human glioblastoma cell line. Biological Rhythm Research, 47(6), pp.865-871.
|
|
|
CN(C)CCOC(C1=CC=CC=C1)C2=CC=CC=C2 |
Approved |
NREM sleep promotion in humans
|
Histamine 1 receptor
|
Histamine 1 blocker
|
Wang, Y.Q., Takata, Y., Li, R., Zhang, Z., Zhang, M.Q., Urade, Y., Qu, W.M. and Huang, Z.L., 2015. Doxepin and diphenhydramine increased non-rapid eye movement sleep through blockade of histamine H1 receptors. Pharmacology Biochemistry and Behavior, 129, pp.56-64.
,
Morioka, E., Kanda, Y., Koizumi, H., Miyamoto, T. and Ikeda, M., 2018. Histamine regulates molecular clock oscillations in human retinal pigment epithelial cells via H1 receptors. Frontiers in endocrinology, 9, p.108.
|
|
|
CCC1=NN2C=CC3=C(C2=C1CCNC(=O)C)CCO3 |
none |
Circadian phase entrainment via MT1/MT2 receptor agonism,
Circadian phase modulation via MT1/MT2 agonism,
Phase shifting in humans (via MT1/MT2 receptor activation),
Phase shift induction in mammals via MT1/MT2 receptor agonism,
sleep-promoting action in freely moving cats
|
MT1
|
MT1 receptor binding,
MT2 receptor ligand
|
Koike, T., Takai, T., Hoashi, Y., Nakayama, M., Kosugi, Y., Nakashima, M., Yoshikubo, S.I., Hirai, K. and Uchikawa, O., 2011. Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8, 9-dihydrofuro [3, 2-c] pyrazolo [1, 5-a] pyridines as melatonin receptor (MT1/MT2) ligands. Journal of medicinal chemistry, 54(12), pp.4207-4218.
|
|
|
C1CN(CCN1CCOCCO)C2=NC3=CC=CC=C3SC4=CC=CC=C42 |
Approved |
improves sleep in insomnia
|
mPer2
,
mPer1
,
CLOCK-BMAL1
|
Core clock modulation,
Bmal1
|
Caruso, V., Geoffroy, P.A., Alfì, G., Miniati, M., Riemann, D., Gemignani, A. and Palagini, L., 2024. Effects of Mood Stabilizers on Sleep and Circadian Rhythms: A Systematic Review. Current Sleep Medicine Reports, 10(3), pp.329-357.
,
Endicott, J., Paulsson, B., Gustafsson, U., Schiöler, H. and Hassan, M., 2008. Quetiapine monotherapy in the treatment of depressive episodes of bipolar I and II disorder: improvements in quality of life and quality of sleep. Journal of affective disorders, 111(2-3), pp.306-319.
|
|
|
C1C2=C(C3=C(C=CC=N3)NC1=O)NC4=C2C=C(C=C4) Br |
none |
Period shortening in mammalian cells
|
GSK-3α/β
|
Highly selective, ATP-competitive inhibition of GSK-3 (both α and β isoforms),
GSK‑3 Inhibition,
Selective GSK-3β Inhibition:,
inhibits glycogen synthase kinase-3β (GSK-3β)
|
Miller, S. and Hirota, T., 2020. Pharmacological interventions to circadian clocks and their molecular bases. Journal of molecular biology, 432(12), pp.3498-3514.
|
|
|
CN1C2=C(C=C(C=C2)Cl)C(=NC(C1=O)O)C3=CC=CC=C3 |
Approved |
Sleep induction and jet lag symptom relief in humans
|
GABAA receptors
|
GABAergic system influence
|
Heel, C., Brogden, R.N., Speight, T.M. and Avery, G.S., 1981. Temazepam: a review of its pharmacological properties and therapeutic efficacy as an hypnotic. Drugs, 21, pp.321-340.
|
|
|
CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCSC)NC=O |
Not approved |
chemotaxis stimulation,
activates G protein-coupled receptors, specifically FPR1,
actin polymerization,
oxidative burst,
Affects circadia nchemotaxis and phagocytosis,
fMLP-mediated activation of human eosinophils is influenced by the circadian clock
|
FPR1
,
FPR2
|
FPR2 full agonist,
FPR1 full agonist
|
Baumann, A., Feilhauer, K., Bischoff, S.C., Froy, O. and Lorentz, A., 2015. IgE-dependent activation of human mast cells and fMLP-mediated activation of human eosinophils is controlled by the circadian clock. Molecular immunology, 64(1), pp.76-81.
|
|
|
C1OC2=C(O1)C=C(C=C2)C3=C(NC(=N3)C4=CC=C(C=C4)C(=O)N)C5=CC=CC=N5 |
none |
Phase shift via Dec1 induction in mammalian cells
|
Dec1 gene expression
|
Activation of activin receptor-like kinase (ALK),
by an immediate-early induction of Dec1
|
Kon, N., Hirota, T., Kawamoto, T., Kato, Y., Tsubota, T. and Fukada, Y., 2008. Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts. Nature cell biology, 10(12), pp.1463-1469.
|
|
|
CC1=NC=C(N1CCO)[N+](=O)[O-] |
None |
Circadian disruption in skeletal muscle and pineal gland (in animals)
|
Microbiota
|
Melatonin synthesis alteration
|
Manickam, R., Oh, H.Y.P., Tan, C.K., Paramalingam, E. and Wahli, W., 2018. Metronidazole causes skeletal muscle atrophy and modulates muscle chronometabolism. International journal of molecular sciences, 19(8), p.2418.
|
|
|
C1=CC(=C(C=C1F)F)C(CN2C=NC=N2)(CN3C=NC=N3)O |
Approved |
Discrupts temporal organization in Candida albicans
|
Lanosterol 14-α-demethylase (fungal CYP51)
|
Inhibits the fungal enzyme lanosterol 14-α-demethylase (CYP51)
|
Nikolenko, M.V., TKh, T. and Paromova, Y.I., 2015. EFFECT OF FLUCONAZOLE ON TEMPORAL ORGANIZATION OF BIOLOGICAL PROPERTIES OF CANDIDA ALBICANS. Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii, (4), pp.30-35.
|
|
|
CCCC(=O)NCCC1=C2C3=CC=CC=C3CCCN2C4=C1C=C(C=C4)OC |
none |
Phase shift disruption in mammals via MT1/MT2 receptor antagonism,
MT2 antagonist; disrupts melatonin signaling (in human receptor models),
Normalization of circadian rhythms in elderly, blind and people with social jet lag.
|
Melatonin receptor
,
MT1
,
MT2
|
MT1 antagonist,
Melatonin receptor binding,
antagonist of melatonin receptors,
MT2 receptor antagonist,
MT1 receptor binding,
MT2 receptor ligand
|
Faust, R., Garratt, P.J., Jones, R., Yeh, L.K., Tsotinis, A., Panoussopoulou, M., Calogeropoulou, T., Teh, M.T. and Sugden, D., 2000. Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6 H-isoindolo [2, 1-a] indoles, 5, 6-dihydroindolo [2, 1-a] isoquinolines, and 6, 7-dihydro-5 H-benzo [c] azepino [2, 1-a] indoles. Journal of medicinal chemistry, 43(6), pp.1050-1061.
,
Sugden, D., Yeh, L.K. and Teh, M.T., 1999. Design of subtype selective melatonin receptor agonists and antagonists. Reproduction Nutrition Development, 39(3), pp.335-344.
|
|
|
[2H]C([2H])(C1=CNC2=C1C=C(C=C2)O[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)C(=O)OC)OC(=O)C)OC(=O)C)OC(=O)C)C([2H])([2H])NC(=O)C |
Not approved |
Circadian rhythm modulation
|
MT1
,
MT2
|
Melatonin receptor binding
|
Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol. 2016 Sep;173(18):2702-25.
|
|
|
C1C2=NN=CN2C3=C(C=C(C=C3)Cl)C(=N1)C4=CC=CC=C4 |
Approved |
sleep modulation in humans
|
GABAA receptors
|
GABAergic system influence
|
Vogel, G.W. and Morris, D., 1992. The effects of estazolam on sleep, performance, and memory: a long‐term sleep laboratory study of elderly insomniacs. The Journal of Clinical Pharmacology, 32(7), pp.647-651.
|
|
|
C1=CC=C(C(=C1)C(=O)O)O |
none |
Period shortening in plants
|
Unknown | Multiple plant targets
|
Plastoquinone interaction
|
Manickam, R., Oh, H.Y.P., Tan, C.K., Paramalingam, E. and Wahli, W., 2018. Metronidazole causes skeletal muscle atrophy and modulates muscle chronometabolism. International journal of molecular sciences, 19(8), p.2418.
|
|
|
CC1C2C(C3C(C(=O)C(=C(C3(C(=O)C2=C(C4=C1C=CC=C4O)O)O)O)C(=O)N)N(C)C)O |
Approved |
restores normal circadian rhythms,
may cause daytime sleepiness,
rescues recognition memory and circadian motor rhythmicity but does not prevent terminal disease in fatal familial insomnia mice
|
Unknown
|
Central clock rescue via microbial community alteration
|
Lavigna, G., Masone, A., Bouybayoune, I., Bertani, I., Lucchetti, J., Gobbi, M., Porcu, L., Zordan, S., Rigamonti, M., Imeri, L. and Restelli, E., 2021. Doxycycline rescues recognition memory and circadian motor rhythmicity but does not prevent terminal disease in fatal familial insomnia mice. Neurobiology of Disease, 158, p.105455.
|
|
|
CC1=C(C=C(N1CCCN2CCOCC2)C3=CC=CC=C3)C(=O)NC4=CC=CC(=C4)C(F)(F)F |
Not approved |
potential circadian entrainment via TRPV4 in eye (mammals)
|
TRPV4 Channel
|
This inhibition of TRPV4-mediated signaling can affect downstream pathways involved in the regulation of the circadian clock.
|
Li, W., Xu, Y., Liu, Z., Shi, M., Zhang, Y., Deng, Y., Zhong, X., Chen, L., He, J., Zeng, J. and Luo, M., 2021. TRPV4 inhibitor HC067047 produces antidepressant-like effect in LPS-induced depression mouse model. Neuropharmacology, 201, p.108834.
|
|
|
CCC(C)C1(C(=O)NC(=O)NC1=O)CC |
Approved |
Indirect circadian disruption via altered sleep–wake timing (in humans)
|
GABAA receptors
|
GABAergic system influence
|
Prinz, P.N., Vitiello, M.V., Raskind, M.A. and Thorpy, M.J., 1990. Sleep disorders and aging. New England Journal of Medicine, 323(8), pp.520-526.
|
|
|
C1=CC=NC(=C1)NS(=O)(=O)C2=CC=C(C=C2)N=NC3=CC(=C(C=C3)O)C(=O)O |
Approved |
circadian clock mediated antitumor effect
|
REV-ERBα
|
Core clock suppression
|
Okazaki, F., Matsunaga, N., Hamamura, K., Suzuki, K., Nakao, T., Okazaki, H., Kutsukake, M., Fukumori, S., Tsuji, Y. and To, H., 2017. Administering xCT inhibitors based on circadian clock improves antitumor effects. Cancer research, 77(23), pp.6603-6613.
|
|
|
CC(C)(C[C@H]1CN(C2=C(O1)C=CC(=C2)C3=CC(=CC(=C3)F)OC(F)F)S(=O)(=O)C4=CC=CC(=C4)C(F)(F)F)C(=O)O |
Not approved |
Circadian modulation via RORγ activation in human immune cells
|
RORB
,
ROR gamma
|
ROR,
RORγ binding
|
Mahalingam, D., Wang, J.S., Hamilton, E.P., Sarantopoulos, J., Nemunaitis, J., Weems, G., Carter, L., Hu, X., Schreeder, M. and Wilkins, H.J., 2019. Phase 1 open-label, multicenter study of first-in-class RORγ agonist LYC-55716 (cintirorgon): safety, tolerability, and preliminary evidence of antitumor activity. Clinical Cancer Research, 25(12), pp.3508-3516.
|