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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
C[C@H](CCCC(C)(C)O)[C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C/3\C[C@H](C[C@@H](C3=C)O)O)C Approved Circadian gene modulation CLOCK-BMAL1 , BMAL1 expression (induction) , Vitamin D3 receptor , Vitamin D binding protein Bmal1, BMAL1 expression modulation, BMAL1 expression modulation, Vitamin D3 receptor, Homeobox protein Hox-A10, Vitamin D-binding protein 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(C)CCC1=CC(=C2C=C(C=CC2=C1)OC)CCNC(=O)C none Phase shifting in humans (via MT1/MT2 receptor activation), Partial agonist MT2 and associated effects MT2 MT2 receptor agonist Ettaoussi, M., Sabaouni, A., Rami, M., Boutin, J.A., Delagrange, P., Renard, P., Spedding, M., Caignard, D.H., Berthelot, P. and Yous, S., 2012. Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I). European journal of medicinal chemistry, 49, pp.310-323.
CCOC(=O)NC1=CC2=C(C=C1)SC3=CC=CC=C3N2C(=O)CCN4CCOCC4 Not approved was found to promote sleep, alter circadian gene expression in the heart, and show a slight trend of increasing free-running periods. Together, these mPer2 , mPer1 , Per2 expression Lenghthen the circadian period, PER gene exspression modulation Han, C., Wirianto, M., Kim, E., Burish, M.J., Yoo, S.H. and Chen, Z., 2021. Clock-modulating activities of the anti-arrhythmic drug moricizine. Clocks & sleep, 3(3), pp.351-365.
CCC(=O)NCCCC1=C(C=CC(=C1)OC)CC2=CC(=CC=C2)OC none Full mt2 rexeptor agonist MT2 MT2 receptor ligand Hu, Y., Zhu, J., Chan, K.H. and Wong, Y.H., 2013. Development of substituted N-[3-(3-methoxylphenyl) propyl] amides as MT2-selective melatonin agonists: Improving metabolic stability. Bioorganic & medicinal chemistry, 21(2), pp.547-552.
CN1CCC23C4C(=O)CCC2(C1CC5=C3C(=C(C=C5)OC)O4)O Approved Oxycodone, like other opioids, can disrupt circadian rhythms, the body's natural 24-hour cycle. Mu opioid receptor , OPRK1 Mu opioid receptor binding Gulledge, M., Carlezon, W.A. Jr, McHugh, R.K., Kinard, E.A., Prerau, M.J. and Chartoff, E.H., 2025. Spontaneous oxycodone withdrawal disrupts sleep, diurnal, and electrophysiological dynamics in rats. PLoS One, 20(1), p.e0312794. , Pierce, B.E., Holter, K., Morton, A., Lekander, A., Bedingham, E., Curry, R. and Gould, R.W., 2022. Effects of oxycodone self-administration on sleep duration and quality in male and female rats. The FASEB Journal, 36(S1), p.R3946.
CCCC(=O)NCCC1=C2C3=CC=CC=C3CN2C4=C1C=C(C=C4)OC none significantly reduced NREM sleep onset latency and transiently increased the time spent in NREM sleep, but did not alter REM sleep latency or the amou, acute sleep-promoting activity MT2 Melatonin receptor binding, MT2 receptor ligand Fisher, S.P. and Sugden, D., 2009. Sleep-promoting action of IIK7, a selective MT2 melatonin receptor agonist in the rat. Neuroscience letters, 457(2), pp.93-96.
C1[C@@H]2[C@H]([C@H]([C@@H](O2)N3C=NC4=C(N=CN=C43)N)O)OP(=O)(O1)O Approved influencing the expression and stability of key circadian clock genes HCN2 , HCN1 , CNGA2 , CNGA3 HCN2 activation, HCN1 activator, CNGA2 activation, Affects melatonin synthesis, CNGA3 activation, OATP4C1 transportation Levine, J.D., Casey, C.I., Kalderon, D.D. and Jackson, F.R., 1994. Altered circadian pacemaker functions and cyclic AMP rhythms in the Drosophila learning mutant dunce. Neuron, 13(4), pp.967-974. , Ono, D., Wang, H., Hung, C.J., Wang, H.T., Kon, N., Yamanaka, A., Li, Y. and Sugiyama, T., 2023. Network-driven intracellular cAMP coordinates circadian rhythm in the suprachiasmatic nucleus. Science Advances, 9(1), p.eabq7032. , O'Neill, J.S. and Reddy, A.B., 2012. The essential role of cAMP/Ca2+ signalling in mammalian circadian timekeeping.
CC1=C(N=C(N=C1N)[C@H](CC(=O)N)NC[C@@H](C(=O)N)N)C(=O)N[C@@H]([C@H](C2=CN=CN2)OC3C(C(C(C(O3)CO)O)O)OC4C(C(C(C(O4)CO)O)OC(=O)N)O)C(=O)N[C@H](C)[C@H]([C@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCCC5=NC(=CS5)C6=NC(=CS6)C(=O)NCCC[S+](C)C)O Approved Circadian rhythm disruption CLOCK-BMAL1 , BMAL1 expression (induction) , Dec1 gene expression Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation, by an immediate-early induction of Dec1 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. , Chen, S.J., Yu, F., Feng, X., Li, Q., Jiang, Y.H., Zhao, L.Q., Cheng, P.P., Wang, M., Song, L.J., Liang, L.M. and He, X.L., 2024. DEC1 is involved in circadian rhythm disruption-exacerbated pulmonary fibrosis. Cell Communication and Signaling, 22(1), p.245.
CCC(=O)N(C1CCN(CC1)CCC2=CC=CC=C2)C3=CC=CC=C3 Approved Circadian entrainment of activity episodes Mu opioid receptor , OPRK1 , OPRD1 Mu opioid receptor binding, Kappa opioid receptor binding, delta opioid receptor binding Du, K., Shi, Q., Zhou, X., Zhang, L., Su, H., Zhang, C., Wei, Z., Liu, T., Wang, L., Wang, X., Cong, B. and Yun, K., 2024. Melatonin attenuates fentanyl-induced behavioral sensitization and circadian rhythm disorders in mice. Physiology & Behavior, 279, p.114523 , Gillman, A.G., Leffel, J.K. 2nd, Kosobud, A.E. and Timberlake, W., 2009. Fentanyl, but not haloperidol, entrains persisting circadian activity episodes when administered at 24- and 31-h intervals. Behavioural Brain Research, 205(1), pp.102–114.
CC12CC(C3C(C1CCC2(C(=O)CO)O)CCC4=CC(=O)C=CC34C)O Approved Disrupts sleep Corticosteroid hormone receptor Affects melatonin synthesis, Melatonin synthesis alteration, Corticosteroid Hormone Receptor Agonist, Glucocorticoid Signaling Jiang, Y., Gen, N., Wang, P., Feng, N. and Lu, X., 2022. Prednisolone induces sleep disorders via inhibition of melatonin secretion by the circadian rhythm in zebrafish. Biomedicine & Pharmacotherapy, 147, p.112590.
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)O)C)C)O)OC)C)C)C)OC Approved Period lengthening in human cells CLOCK-BMAL1 de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation, mTOR signaling inhibition 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(C)C1=C(C(=CC=C1)C(C)C)O Approved Phase advance GABAA receptors GABA A receptor binding Challet, E., Gourmelen, S., Pevet, P., Oberling, P. and Pain, L., 2007. Reciprocal relationships between general (propofol) anesthesia and circadian time in rats. Neuropsychopharmacology, 32(3), pp.728–735. , Bienert, A., Kusza, K., Wawrzyniak, K., Grześkowiak, E., Kokot, Z.J., Matysiak, J., Grabowski, T., Wolc, A., Wiczling, P. and Regulski, M., 2010. Assessing circadian rhythms in propofol PK and PD during prolonged infusion in ICU patients. Journal of Pharmacokinetics and Pharmacodynamics, 37, pp.289–304. , Touitou, Y., Mauvieux, B., Reinberg, A. and Dispersyn, G., 2016. Disruption of the circadian period of body temperature by the anesthetic propofol. Chronobiology International, 33(9), pp.1247–1254.
CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OCCCCOC3=CC=C(C=C3)C4=CC=C(C=C4)C(=O)O Not approved restores normal circadian rhythms, MT1 agonist with poorly described MT1 selective MT1A receptor agonist Jockers, R., Delagrange, P., Dubocovich, M.L., Markus, R.P., Renault, N., Tosini, G., Cecon, E. and Zlotos, D.P., 2016. Update on melatonin receptors: IUPHAR Review 20. British Journal of Pharmacology, 173(18), pp.2702–2725.
C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@@]4([C@]3([C@H](C[C@@]2([C@]1(C(=O)CO)O)C)O)F)C Approved Resetting of circadian time in peripheral tissues Corticosteroid hormone receptor Corticosteroid Hormone Receptor Agonist, Glucocorticoid Signaling Barnea, M., Madar, Z. and Froy, O., 2013. Dexamethasone induces high-amplitude rhythms in preadipocytes, but hinders circadian expression in differentiated adipocytes. Chronobiology International, 30(6), pp.837-842. , Balsalobre, A., Brown, S.A., Marcacci, L., Tronche, F., Kellendonk, C., Reichardt, H.M., Schutz, G. and Schibler, U., 2000. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science, 289(5488), pp.2344-2347.
CNC1(CCCCC1=O)C2=CC=CC=C2Cl Approved Modulation of circadian gene expression and CLOCK:BMAL1 transcriptional activity in neuronal cells and rats CLOCK-BMAL1 Core clock modulation Bellet, M.M., Vawter, M.P., Bunney, B.G., Bunney, W.E. and Sassone-Corsi, P., 2011. Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression. PLoS One, 6(8), p.e23982. , Zhuo, C., Tian, H., Li, G., Chen, M., Jiang, D., Lin, X., Xu, Y. and Wang, W., 2019. Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment-resistant depression: a protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans. Brain and Behavior, 9(11), p.e01423 , Mihara, T., Kikuchi, T., Kamiya, Y., Koga, M., Uchimoto, K., Kurahashi, K. and Goto, T., 2012. Day or night administration of ketamine and pentobarbital differentially affect circadian rhythms of pineal melatonin secretion and locomotor activity in rats. Anesthesia & Analgesia, 115(4), pp.805–813.
CN1CCN(CC1)C(=O)OC2C3=NC=CN=C3C(=O)N2C4=NC=C(C=C4)Cl Approved helps with sleep, it doesn't necessarily reset or re-establish the body's internal clock Unknown Sleep promotion Krystal, A.D., Walsh, J.K., Laska, E., Caron, J., Amato, D.A., Wessel, T.C. and Roth, T., 2003. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep, 26(7), pp.793-799.
CC(=O)NCCC1=C(CC2=C1C3=C(C=C2)OCC3)CC4CCCCC4 Not approved Discrupts temporal organization in Candida albicans, Full mt2 rexeptor agonist MT2 MT2 receptor agonist, MT2 receptor ligand Koike, T., Hoashi, Y., Takai, T., Nakayama, M., Yukuhiro, N., Ishikawa, T., Hirai, K. and Uchikawa, O., 2011. 1, 6-Dihydro-2 H-indeno [5, 4-b] furan Derivatives: Design, Synthesis, and Pharmacological Characterization of a Novel Class of Highly Potent MT2-Selective Agonists. Journal of medicinal chemistry, 54(9), pp.3436-3444.
CC1=CC(=C2C=C(C=C(C2=N1)F)F)NC(=O)NC3=CC=C(C=C3)N(C)C Not approved can attenuate the sleep-promoting effects of the OX2R antagonist orexin receptor subtypes (OX1 and OX2) OX₁R Antagonism Morairty, S.R., Revel, F.G., Malherbe, P., Moreau, J.L., Valladao, D., Wettstein, J.G., Kilduff, T.S. and Borroni, E., 2012. Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PloS one, 7(7), p.e39131.
COC1=CC2=C(C=CC=C2CCNC(=O)C(F)F)C=C1 Not approved MT1 agonist with poorly described, increases the amplitude of circadian rhythm activity in mice with corticosterone-induced depression/anxiety MT1 MT1 receptor binding Ettaoussi, M., Sabaouni, A., Rami, M., Boutin, J.A., Delagrange, P., Renard, P., Spedding, M., Caignard, D.H., Berthelot, P. and Yous, S., 2012. Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I). European journal of medicinal chemistry, 49, pp.310-323.
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.