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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
CN(C)CCCN1C2=CC=CC=C2SC3=C1C=C(C=C3)Cl Approved NPAS2 Unknown Nagayama, H., Takagi, A., Sakurai, Y., Nishiwaki, K. and Takahashi, R., 1978. Chronopharmacological study of neuroleptics: II. Circadian susceptibility rhythm to chlorpromazine. Psychopharmacology, 58, pp.49-53.
CN(C)C(=O)NC1CCC(CC1)CCN2CCN(CC2)C3=C(C(=CC=C3)Cl)Cl Approved D2R (dopamine receptor) Dopamine receptor binding Nyitrai, G., et al. 2021. Cariprazine modulates sleep architecture in rats. Journal of Psychopharmacology, 35(3), pp.303-310.
C1CN(CCC1N2C3=CC=CC=C3NC2=O)CCCC(=O)C4=CC=C(C=C4)F Approved D2R (dopamine receptor) Dopamine receptor binding, Dopamine receptor agonist Altenhofen, S. and Bonan, C.D., 2022. Zebrafish as a Tool in the Study of Sleep and Memory-related Disorders. Current neuropharmacology, 20(3), pp.540-549.
CN1CC2C(C1)C3=C(C=CC(=C3)Cl)OC4=CC=CC=C24 Approved Induces resless legs syndrome 5-HT7 5-HT7 binding Delcourte, S., Abrial, E., Etiévant, A., Rovera, R., Arnt, J., Didriksen, M. and Haddjeri, N., 2017. Asenapine modulates mood‐related behaviors and 5‐HT 1A/7 receptors‐mediated neurotransmission. CNS Neuroscience & Therapeutics, 23(6), pp.518-525. , Colita, C.I., Hermann, D.M., Filfan, M., Colita, D., Doepnner, T.R., Tica, O., Glavan, D. and Popa-Wagner, A., 2024. Optimizing Chronotherapy in Psychiatric Care: The Impact of Circadian Rhythms on Medication Timing and Efficacy. Clocks & Sleep, 6(4), pp.635-655. , McCall, W.V., Riley, M.A., Hodges, C., McCloud, L., Phillips, M. and Rosenquist, P.B., 2014. Asenapine-induced restless legs syndrome: differentiation from akathisia. Journal of Clinical Sleep Medicine, 10(12), pp.1341-1342.
C1=CC=C2C3=C4C(=CC=C3)C5=CC=CC=C5C4=CC2=C1 None mPer2 , mPer1 , CRY1-PER2 complex , CRY1 , CLOCK-BMAL1 Disruption of circadian clock, Bmal1, Interferes with CLOCK–BMAL1, Targets BMAL1–CLOCK DNA-binding activity, aryl hydrocarbon receptor (AhR) binding Schmitt, E. E., Barhoumi, R., Metz, R. P., & Porter, W. W. (2017). Circadian Regulation of Benzo[a]Pyrene Metabolism and DNA Adduct Formation in Breast Cells and the Mouse Mammary Gland. Molecular Pharmacology, 91(3), 178–188.
COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC Approved potential period alteration via EGFR/JAK2 inhibition CLOCK-BMAL1 , BMAL1 expression (induction) , JAK2 , EGFR inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase 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=CC2=C(S1)NC3=CC=CC=C3N=C2N4CCN(CC4)C Approved Unknown Disruption of circadian clock, Unknown Romo‐Nava, F., Buijs, F.N., Valdés‐Tovar, M., Benítez‐King, G., Basualdo, M., Perusquía, M., Heinze, G., Escobar, C. and Buijs, R.M., 2017. Olanzapine‐induced early cardiovascular effects are mediated by the biological clock and prevented by melatonin. Journal of Pineal Research, 62(4), p.e12402. , Vidarsdottir, S., Roelfsema, F., Frolich, M. and Pijl, H., 2009. Olanzapine shifts the temporal relationship between the daily acrophase of serum prolactin and cortisol concentrations rhythm in healthy men. Psychoneuroendocrinology, 34(5), pp.705-712.
CCCCCCCCCC(=O)OCCN1CCN(CC1)CCCN2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F Approved Unknown Binding to rat brainα- andβ-adrenergic, muscarinic cholinergic, dopamine and opiate receptors Naber, D., Wirz-Justice, A. and Kafka, M.S., 1982. Chronic fluphenazine treatment modifies circadian rhythms of neurotransmitter receptor binding in rat brain. Journal of Neural Transmission, 55, pp.277-288.
CCN1CCCC1CNC(=O)C2=C(C=CC(=C2)S(=O)(=O)N)OC Approved Modulates insulin release rhtyhms D2R (dopamine receptor) Dopamine receptor binding Wei, H., Zapata, R.C., Lopez-Valencia, M., Aslanoglou, D., Farino, Z.J., Benner, V., Osborn, O., Freyberg, Z. and McCarthy, M.J., 2020. Dopamine D2 receptor signaling modulates pancreatic beta cell circadian rhythms. Psychoneuroendocrinology, 113, p.104551.
CC1=C(C(=O)N2CCCCC2=N1)CCN3CCC(CC3)C4C5=C(C=C(C=C5)F)ON4 Approved mPer2 , mPer1 , CRY1-PER2 complex , CRY1 , CRY1 , REV-ERBα Core clock modulation, PER gene exspression modulation, CRY gene expression modulation, BMAL1 expression modulation Zapata, R.C., Silver, A., Yoon, D., Chaudry, B., Libster, A., McCarthy, M.J. and Osborn, O., 2022. Adverse effects of antipsychotic drugs on metabolism depend on drug dosing and feeding times. medRxiv, pp.2022-02. , Cherukalady, R., Kumar, D., Basu, P. and Singaravel, M., 2017. Risperidone resets the circadian clock in mice. Biological Rhythm Research, 48(4), pp.583-591.
CC(=O)[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2C=C(C4=CC(=O)[C@@H]5C[C@@H]5[C@]34C)Cl)C)O Approved Circadian gene modulation in human U2OS cells CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) Bmal1, de-repressing 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.
CC1=NC(=NC=C1OC[C@]2(C[C@H]2C(=O)NC3=NC=C(C=C3)F)C4=CC(=CC=C4)F Approved Orexin Receptors OX1R and OX2R Orexin Receptor Antagonism https://pubmed.ncbi.nlm.nih.gov/33336219/
C1CN(CCN1CCOCCO)C(C2=CC=CC=C2)C3=CC=C(C=C3)Cl Approved Histamine 1 receptor Histamine 1 blocker Spahr, L., Coeytaux, A., Giostra, E., Hadengue, A. and Annoni, J.M., 2007. Histamine H1 blocker hydroxyzine improves sleep in patients with cirrhosis and minimal hepatic encephalopathy: a randomized controlled pilot trial. Official journal of the American College of Gastroenterology| ACG, 102(4), pp.744-753.
C1CN(CC=C1N2C3=CC=CC=C3NC2=O)CCCC(=O)C4=CC=C(C=C4)F Approved D2R (dopamine receptor) Dopamine receptor binding, Dopamine receptor binding, Dopamine receptor antagonist Cugini, P., Delogu, G., Casula, M.A., Gatta, L., Cascioli, C. and Di Palma, L., 1991. Anaesthesia‐induced dissociation between the circadian rhythms of blood pressure and heart rate. Biological Rhythm Research, 22(4), pp.333-340.
CC1=CC=C(C=C1)C2=C(N3C=C(C=CC3=N2)C)CC(=O)N(C)C Approved GABAA receptors Hypnotic effect, GABAergic system influence Keuroghlian, A.S., Barry, A.S. and Weiss, R.D., 2012. Circadian dysregulation, zolpidem dependence, and withdrawal seizure in a resident physician performing shift work. The American Journal on Addictions/American Academy of Psychiatrists in Alcoholism and Addictions, 21(6), p.576. , Keating, G.M., 2005. Zolpidem: a review of its use in the management of insomnia. CNS Drugs, 19(1), pp.65-89. , Copinschi, G., Akseki, E., Moreno-Reyes, R., Leproult, R., L'Hermite-Balériaux, M., Caufriez, A., Vertongen, F. and Cauter, E.V., 1995. Effects of Bedtime Administration of Zolpidem on Orcadian and Sleep-Related Hormonal Profiles in Normal Women. Sleep, 18(6), pp.417-424.
CCC(=O)N(C1=CC=CC=C1)C2(CCN(CC2)CCC(=O)OC)C(=O)OC Approved REM sleep suppression in humans Mu opioid receptor , OPRK1 , OPRD1 Unknown, Mu opioid receptor binding, Kappa opioid receptor binding, delta opioid receptor binding Bonafide, C.P., Aucutt-Walter, N., Divittore, N., King, T., Bixler, E.O. and Cronin, A.J., 2008. Remifentanil inhibits rapid eye movement sleep but not the nocturnal melatonin surge in humans. Anesthesiology, 108(4), pp.627–633. , Wenk, M., Pöpping, D.M., Chapman, G., Grenda, H. and Ledowski, T., 2013. Long-term quality of sleep after remifentanil-based anaesthesia: a randomized controlled trial. British Journal of Anaesthesia, 110(2), pp.250–257
CC(CN1C2=CC=CC=C2SC3=CC=CC=C31)N(C)C Approved Histamine 1 receptor Histamine 1 blocker Masse, M., Henry, H., Cuvelier, E., Pinçon, C., Pavy, M., Beeuwsaert, A., Barthélémy, C., Cuny, D., Gautier, S., Kambia, N. and Lefebvre, J.M., 2022, January. Sleep medication in older adults: identifying the need for support by a community pharmacist. In Healthcare (Vol. 10, No. 1, p. 147). MDPI. , Cantisani, C., Ricci, S., Grieco, T., Paolino, G., Faina, V., Silvestri, E. and Calvieri, S., 2013. Topical promethazine side effects: our experience and review of the literature. BioMed research international, 2013(1), p.151509.
CC1CCC(CN1C(=O)C2=C(C=CC(=C2)C)C3=NC=CC=N3)COC4=NC=C(C=C4)F Not approved Orexin Receptors OX1R and OX2R Orexin Receptor Antagonism Hoyer, D., Dürst, T., Fendt, M., Jacobson, L.H., Betschart, C., Hintermann, S., Behnke, D., Cotesta, S., Laue, G., Ofner, S. and Legangneux, E., 2013. Distinct effects of IPSU and suvorexant on mouse sleep architecture. Frontiers in neuroscience, 7, p.235.
CC1=C(C=CC2=C1N=C(N2)[C@@]3(CCCN3C(=O)C4=C(C=CC(=C4)OC)N5N=CC=N5)C)Cl Approved Orexin Receptors OX1R and OX2R Orexin Receptor Antagonism Amodeo, L.R., Wills, D.N., Benedict, J. and Ehlers, C.L., 2025. Effects of daridorexant on rest/wake activity patterns and drinking in adult rats exposed to chronic ethanol vapor in adolescence. Alcohol, 124, pp.35-46.
C[C@]1(C2=C(CC(CC2=O)(C)C)NC3=NNC(=C31)C(F)(F)F)C4=CC=CC=C4 Not approved Period shortening in mammalian cells GSK-3α/β Selective GSK-3β Inhibition:, Circadian Clock Impact Wagner, F.F., Bishop, J.A., Gale, J.P., Shi, X., Walk, M., Ketterman, J., Patnaik, D., Barker, D., Walpita, D., Campbell, A.J. and Nguyen, S., 2016. Inhibitors of glycogen synthase kinase 3 with exquisite kinome-wide selectivity and their functional effects. ACS Chemical Biology, 11(7), pp.1952-1963.
C1C(=S)N(C2=C(C=C(C=C2)Cl)C(=N1)C3=CC=CC=C3F)CC(F)(F)F Approved GABAA receptors GABAergic system influence Hilbert, J.M., Chung, M., Maier, G., Gural, R., Symchowicz, S. and Zampaglione, N., 1984. Effect of sleep on quazepam kinetics. Clinical Pharmacology & Therapeutics, 36(1), pp.99-104.
C(C(Cl)(Cl)Cl)(O)O Not approved GABAA receptors GABAergic system influence Ashrafi, M.R., Mohammadi, M., Tafarroji, J., Shabanian, R., Salamati, P. and Zamani, G.R., 2010. Melatonin versus chloral hydrate for recording sleep EEG. european journal of paediatric neurology, 14(3), pp.235-238.
C1=NC(=C2C(=N1)N(C=N2)C3C(C(C(O3)CO)O)O)N Not approved ADORA2B A2B receptor agonist. Hinz, S., Lacher, S.K., Seibt, B.F. and Müller, C.E., 2014. BAY60-6583 acts as a partial agonist at adenosine A2B receptors. The Journal of pharmacology and experimental therapeutics, 349(3), pp.427-436.
CN1CCN(CC1)C(=O)OC2C3=NC=CN=C3C(=O)N2C4=NC=C(C=C4) Cl Approved GABAA receptors GABA A receptor binding, GABAergic system influence Masse, M., Henry, H., Cuvelier, E., Pinçon, C., Pavy, M., Beeuwsaert, A., Barthélémy, C., Cuny, D., Gautier, S., Kambia, N. and Lefebvre, J.M., 2022, January. Sleep medication in older adults: identifying the need for support by a community pharmacist. In Healthcare (Vol. 10, No. 1, p. 147). MDPI.
CN(C)CCC=C1C2=CC=CC=C2COC3=CC=CC=C31.Cl Approved GABAA receptors GABA A receptor binding, GABAergic system influence Yeung, W.F., Chung, K.F., Yung, K.P. and Ng, T.H.Y., 2015. Doxepin for insomnia: a systematic review of randomized placebo-controlled trials. Sleep medicine reviews, 19, pp.75-83.