|
|
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.
|
|
|
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.
|
|
|
C1=NC(=C2C(=N1)N(C=N2)[C@H]3[C@@H]([C@@H]([C@H](O3)CO)O)O)N |
Approved |
Phase shift modulation and period regulation via adenosine receptor signaling (in mice and mammals)
|
Adenosine A1, A2A, A2B, and A3 Receptors
|
Activation of Adenosine Receptors
|
Jagannath, A., Varga, N., Dallmann, R., Rando, G., Gosselin, P., Ebrahimjee, F., Taylor, L., Mosneagu, D., Stefaniak, J., Walsh, S. and Palumaa, T., 2021. Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice. Nature communications, 12(1), p.2113.
|
|
|
CCN(C1=CC=CC(=C1)C2=CC=NC3=C(C=NN23)C#N)C(=O)C |
Approved |
Affects melatonin synthsis,
increases melatonin synthesis
|
GABAA receptors
|
GABA A receptor binding,
GABAergic system influence
|
Morera, A.L., Abreu-Gonzalez, P. and Henry, M., 2009. Zaleplon increases nocturnal melatonin secretion in humans. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33(6), pp.1013-1016.
|
|
|
C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)O)C)C)[C@@H]2[C@H]1C)C)C(=O)O |
Not approved |
Modulation of clock gene expression and metabolic rhythm regulation in liver (in mammals)
|
ROR gamma
|
PTEN,
ROCK,
p53
|
Kojetin, D.J. and Burris, T.P., 2014. REV-ERB and ROR nuclear receptors as drug targets. Nature reviews Drug discovery, 13(3), pp.197-216.
,
Kwon, E.Y., Shin, S.K. and Choi, M.S., 2018. Ursolic acid attenuates hepatic steatosis, fibrosis, and insulin resistance by modulating the circadian rhythm pathway in diet-induced obese mice. Nutrients, 10(11), p.1719.
,
Zahran, E.M., Mohamad, S.A., Elsayed, M.M., Hisham, M., Maher, S.A., Abdelmohsen, U.R., Elrehany, M., Desoukey, S.Y. and Kamel, M.S., 2024. Ursolic acid inhibits NF-κB signaling and attenuates MMP-9/TIMP-1 in progressive osteoarthritis: a network pharmacology-based analysis. RSC advances, 14(26), pp.18296-18310.
|
|
|
CC1=CC(=NO1)NS(=O)(=O)C2=CC=C(C=C2)N |
Approved |
Circadian phase shift and dysrhythmia in eclosion rhythm in Drosophila melanogaster
|
mPer2
,
mPer1
,
CRY1-PER2 complex
,
CRY1
,
CLOCK-BMAL1
|
Core clock suppression
|
Yu, Z., Shen, J., Li, Z., Yao, J., Li, W., Xue, L., Vandenberg, L.N. and Yin, D., 2020. Obesogenic effect of sulfamethoxazole on Drosophila melanogaster with simultaneous disturbances on eclosion rhythm, glucolipid metabolism, and microbiota. Environmental Science & Technology, 54(9), pp.5667-5675.
|
|
|
CCCC1CC(N(C1)C)C(=O)NC(C2C(C(C(C(O2)SC)O)O)O)C(C)O |
not approved |
alone caused a long circadian period. However, the degree of lengthening was less than with Fe deficiency alone
|
Fe deficiency
|
Unknown
|
Chen, Y.Y., Wang, Y., Shin, L.J., Wu, J.F., Shanmugam, V., Tsednee, M., Lo, J.C., Chen, C.C., Wu, S.H. and Yeh, K.C., 2013. Iron is involved in the maintenance of circadian period length in Arabidopsis. Plant physiology, 161(3), pp.1409-1420.
|
|
|
C1=CC=C(C=C1)C(C2=CC=CC=C2)C(=O)N[C@H](CCCN=C(N)N)C(=O)NCC3=CC=C(C=C3)CNC(=O)N.C(=O)(C(F)(F)F)O |
none |
Phase shift via Y1 receptor antagonism in rodents
|
Neuropeptide Y Y1 receptor
|
Neuropeptide Y1 receptor binding
|
Cohen, S., Vainer, E., Matar, M.A., Kozlovsky, N., Kaplan, Z., Zohar, J., Mathé, A.A. and Cohen, H., 2015. Diurnal fluctuations in HPA and neuropeptide Y-ergic systems underlie differences in vulnerability to traumatic stress responses at different zeitgeber times. Neuropsychopharmacology, 40(3), pp.774-790.
|
|
|
CC1=C(C(=CC=C1)C(C)C2=CN=CN2)C |
Approved |
Altered expression of clock genes in mice
|
mPer2
,
mPer1
,
CRY1-PER2 complex
|
Core clock modulation
|
Huang, X., Lin, D., Sun, Y., Wu, A. and Wei, C., 2021. Effect of dexmedetomidine on postoperative sleep quality: a systematic review. Drug design, development and therapy, pp.2161-2170.
|