Logo

List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
C1=CC=C2C(=C1)C3=NN(C4=CC=CC(=C43)C2=O)CCO None Period lengthening JNK JNK kinase mediated circadian rhythm modulation Park, W.R., Choi, B., Kim, Y.J., Kim, Y.H., Park, M.J., Kim, D.I., Choi, H.S. and Kim, D.K., 2022. Melatonin regulates iron homeostasis by inducing hepcidin expression in hepatocytes. International Journal of Molecular Sciences, 23(7), p.3593. , Wu, H.M., Shen, Q.Y., Fang, L., Zhang, S.H., Shen, P.T., Liu, Y.J. and Liu, R.Y., 2016. JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis. Journal of Pineal Research, 60(4), pp.415–423.
CC(=O)NCCC1=C(NC2=C1C=C(C=C2)OC)CC3=CC=CC=C3 none Circadian phase entrainment via MT1/MT2 receptor agonism MT2 MT2 receptor ligand Dubocovich, M.L., Masana, M.I., Iacob, S. and Sauri, D.M., 1997. Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn-Schmiedeberg's archives of pharmacology, 355, pp.365-375.
C1CCNC(C1)C(C2=CC(=NC3=C2C=CC=C3C(F)(F)F)C(F)(F)F)O Approved causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression, Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythm PER2 gene expression Per2 expression alteration Koo, J., Choe, H.K., Kim, H.D., Chun, S.K., Son, G.H. and Kim, K., 2015. Effect of mefloquine, a gap junction blocker, on circadian period2 gene oscillation in the mouse suprachiasmatic nucleus ex vivo. Endocrinology and Metabolism, 30(3), pp.361-370.
CC(=O)O[C@H]1[C@H]([C@@H]2[C@]([C@H](CCC2(C)C)O)([C@@]3([C@@]1(O[C@@](CC3=O)(C)C=C)C)O)C)O Not approved Circadian rhythm induction mPer2 , mPer1 , Per2 expression , Per 1 expression (gene) , Per 1 (Rat gene) , Per 2 (gene Rat) PER gene exspression modulation Yagita, K. and Okamura, H., 2000. Forskolin induces circadian gene expression of rPer1, rPer2 and dbp in mammalian rat-1 fibroblasts. FEBS letters, 465(1), pp.79-82.
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.
C1CCC(CC1)(C2=CC=CC=C2)N3CCCCC3 Not approved Disrupts circadian rhtyhms, depressant NMDA receptor , NMDA receptor Glutamate receptor ionotropic, NMDA 2B, Glutamate receptor ionotropic, NMDA 3A antagonist, Glutamate receptor ionotropic, NMDA 1, NMDA receptor antagonist, Glutamate receptor ionotropic, NMDA 2A, USigma non-opioid intracellular receptor 1 Mitchell, E.J., Brett, R.R., Armstrong, J.D., Sillito, R.R. and Pratt, J.A., 2020. Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system–implications for the 3Rs and preclinical drug discovery. Journal of Psychopharmacology, 34(7), pp.709-715.
CC1=CC(=C(C(=C1)C)N2CC(CC2=O)C(=O)N3CCC(CC3)(C4=CNC5=CC=CC=C45)C6=CNC7=CC=CC=C67)C none lengthens the period of the U2-OS circadian rhythm, decreases the transcription of clock-controlled genes in a concentration-dependent manner CRY1 CRY1 stabilizer, binds CRY1 ubiquitination site, Selective stabilizer of CRY1 Gül, Z.M., Aydoğan, S., Sürme, S., Efendi, S.N.H., Özcan, O., Uyanık, E., Baris, I., Gül, S. and Kavakli, I.H., 2025. M54 selectively stabilizes the circadian clock component of CRY1 and enhances the period of circadian rhythm at cellular level. Journal of Biological Chemistry, 301(7).
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.