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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
CC(=O)NCCC1=C(NC2=C1C=C(C=C2)OC)C3=CC=CC=C3 not approved MT1/MT2 receptor agonist; potential circadian phase modulation in mammals Melatonin receptor , MT1 , MT2 MT1 receptor binding, MT2 receptor ligand, Melatonin agonist Radogna, F., Paternoster, L., De Nicola, M., Cerella, C., Ammendola, S., Bedini, A., Tarzia, G., Aquilano, K., Ciriolo, M. and Ghibelli, L., 2009. Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes. Toxicology and Applied Pharmacology, 239(1), pp.37–45. , Mor, M., Spadoni, G., Di Giacomo, B., Diamantini, G., Bedini, A., Tarzia, G., Plazzi, P.V., Rivara, S., Nonno, R., Lucini, V., Pannacci, M., Fraschini, F. and Stankov, B.M., 2001. Synthesis, pharmacological characterization and QSAR studies on 2-substituted indole melatonin receptor ligands. Bioorganic & Medicinal Chemistry, 9(4), pp.1045–1057.
CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC.Cl approved restores normal circadian rhythms, Resynchronization of the circadian clock, potentially improving sleep quality and alleviating symptoms associated with sleep disturbances. Melatonin receptor Melatonin receptor binding Tchekalarova, J., Stoynova, T., Ilieva, K., Mitreva, R. and Atanasova, M., 2018. Agomelatine treatment corrects symptoms of depression and anxiety by restoring the disrupted melatonin circadian rhythms of rats exposed to chronic constant light. Pharmacology Biochemistry and Behavior, 171, pp.1–9. , Mairesse, J., Silletti, V., Laloux, C., Zuena, A.R., Giovine, A., Consolazione, M., van Camp, G., Malagodi, M., Gaetani, S., Cianci, S., Catalani, A., Mennuni, G., Mazzetta, A., van Reeth, O., Gabriel, C., Mocaër, E., Nicoletti, F., Morley-Fletcher, S. and Maccari, S., 2013. Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats. International Journal of Neuropsychopharmacology, 16
CC(=O)NCCC1=CNC2=CC=CC=C21 Not approved Partial MT2 receptor agonist; modulates circadian signaling in retina (mammals) Melatonin receptor , MT1 Melatonin receptor binding, MT1 receptor binding Backlund, P.S., Urbanski, H.F., Doll, M.A., Hein, D.W., Bozinoski, M., Mason, C.E., Coon, S.L. and Klein, D.C., 2017. Daily rhythm in plasma N-acetyltryptamine. Journal of Biological Rhythms, 32(3), pp.195–211. , Pohanka, M., 2022. New uses of melatonin as a drug: a review. Current Medicinal Chemistry, 29(20), pp.3622–3637.
CC(=O)NCCC1=C2C=C(C=CC2=CC(=C1)O)O None Weak MT1/MT2 agonist MT1 , MT2 Melatonin receptor binding, MT1 receptor binding, MT2 receptor ligand Bogaards, J.J., Hissink, E.M., Briggs, M., Weaver, R., Jochemsen, R., Jackson, P., Bertrand, M. and van Bladeren, P.J., 2000. Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling. European Journal of Pharmaceutical Sciences, 12(2), pp.117–124.
[2H]C([2H])(C1=CC=CC2=C1C=C(C=C2)OC)C([2H])([2H])NC(=O)C Not approved derivative of chronobiotic agomelatine (MT1/MT2) Melatonin receptor Melatonin receptor binding De Berardis, D., Marini, S., Fornaro, M., Srinivasan, V., Iasevoli, F., Tomasetti, C., Valchera, A., Perna, G., Quera-Salva, M.A., Martinotti, G. and Di Giannantonio, M., 2013. The melatonergic system in mood and anxiety disorders and the role of agomelatine: implications for clinical practice. International Journal of Molecular Sciences, 14(6), pp.12458–12483.
[2H]C([2H])([2H])C(NC([2H])([2H])C([2H])([2H])C(C1=C2)=CNC1=CC=C2OC)=O not approved MT1/MT2 receptor agonist MT1 , MT2 Melatonin receptor binding, MT1 receptor binding, MT2 receptor ligand Fourtillan, J.B., Brisson, A.M., Gobin, P., Ingrand, I., Decourt, J.P. and Girault, J., 2000. Bioavailability of melatonin in humans after day-time administration of D(7) melatonin. Biopharmaceutics & Drug Disposition, 21(1), pp.15–22.
[2H]C([2H])([2H])C([2H])([2H])C(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3 Approved MT1/MT2 receptor agonist Melatonin receptor Melatonin receptor binding McGechan, A. and Wellington, K., 2005. Ramelteon. CNS Drugs, 19(12), pp.1057–1065; discussion 1066–1067.
CCCCC(=O)NCCC1=C(NC2=CC=CC=C21)CC3=CC=CC=C3 Not approved MT2 antagonist; disrupts melatonin signaling (in human receptor models) Melatonin receptor Melatonin receptor binding Behrens, U.D., Douglas, R.H., Sugden, D., Davies, D.J. and Wagner, H.J., 2000. Effect of melatonin agonists and antagonists on horizontal cell spinule formation and dopamine release in a fish retina. Cell and Tissue Research, 299(3), pp.299–306.
CC(=O)NCCN1CCC2=C1C3=C(C=C2)OCC3 Not approved Sleep-promoting and circadian phase-altering effects in mice Melatonin receptor , MT1 MT1 receptor binding Beresford, I.J., Harvey, F.J., Hall, D.A. and Giles, H., 1998. Pharmacological characterisation of melatonin MT1 receptor-mediated stimulation of [³⁵S]-GTPγS binding. Biochemical Pharmacology, 56(9), pp.1167–1174. , Fratter, A., 2013. Nanoemulsion technology for sublingual delivery of melatonin: characterization and preliminary data on a new administration system. In: New Developments in Melatonin Research. Nova Science Publishers, New York. ISBN: 978-1-62618-880-8.
[2H]C([2H])([2H])CC(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3 Approved Melatonin receptor Melatonin receptor binding Miyamoto, M., 2009. Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neuroscience & Therapeutics, 15(1), pp.32–51.
CC(=O)NCCC1=CNC2=CC(=C(C=C21)OC)Cl Not approved Melatonin receptor Melatonin receptor binding Kumari, Y., Choo, B.K.M., Shaikh, M.F. and Othman, I., 2019. Melatonin receptor agonist Piper betle L. ameliorates dexamethasone-induced early life stress in adult zebrafish. Experimental and Therapeutic Medicine, 18(2), pp.1095–1102.
[2H]C([2H])([2H])C([2H])([2H])C(=O)NC[C@@H]1C[C@H]1C2=C3CCOC3=CC=C2 not approved Melatonin receptor Melatonin receptor binding Russak, E.M. and Bednarczyk, E.M., 2019. Impact of deuterium substitution on the pharmacokinetics of pharmaceuticals. Annals of Pharmacotherapy, 53(2), pp.211–216 , Lavedan, C., Forsberg, M. and Gentile, A.J., 2015. Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology, 91, pp.142–147
CC(=O)NCCC1=C(OC2=C1C=C(C=C2)OC)CC3=CC(=CC=C3)OC Not approved UNKNOWN Melatonin receptor Melatonin receptor binding 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. , Boutin, J.A., Witt-Enderby, P.A., Sotriffer, C. and Zlotos, D.P., 2020. Melatonin receptor ligands: a pharmaco-chemical perspective. Journal of Pineal Research, 69(2), p.e12672. , Williams III, W.P., McLin III, D.E., Dressman, M.A. and Neubauer, D.N., 2016. Comparative review of approved melatonin agonists for the treatment of circadian rhythm sleep‐wake disorders. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 36(9), pp.1028-1041.
CCCCCC1=CC(=C(C(=C1)O)CC=C(C)CCC=C(C)C)O Not approved Cannabinoid receptor Core clock modulation, Unknown Pertwee, R.G. (Ed.), 2014. Handbook of Cannabis. Oxford University Press, USA.
CCCCCC1=CC(=C2C3C=C(CCC3C(OC2=C1)(C)C)C)O Not approved Cannabinoid receptor Core clock modulation Kaul, M., Zee, P.C. and Sahni, A.S., 2021. Effects of cannabinoids on sleep and their therapeutic potential for sleep disorders. Neurotherapeutics, 18(1), pp.217–227.
CCCCCC1=CC(=C(C(=C1)O)C2C=C(CCC2C(=C)C)C)O Not approved RORA , NR1D1 , RORB Disruption of circadian clock, Core clock modulation Lafaye, G., Desterke, C., Marulaz, L. and Benyamina, A., 2019. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addiction Biology, 24(5), pp.921–934. , Koch, M., Dehghani, F., Habazettl, I., Schomerus, C. and Korf, H.W., 2006. Cannabinoids attenuate norepinephrine-induced melatonin biosynthesis in the rat pineal gland by reducing arylalkylamine N-acetyltransferase activity without involvement of cannabinoid receptors. Journal of Neurochemistry, 98(1), pp.267–278.
CCCCCC1=CC(=C2C=CC(OC2=C1)(C)CCC=C(C)C)O Not approved non-psychoactive cannabinoid, can influence circadian rhythms through its interaction with the endocannabinoid system (ECS) and potentially by modulat Cannabinoid receptor Unknown Hodges, E.L. and Ashpole, N.M., 2019. Aging circadian rhythms and cannabinoids. Neurobiology of aging, 79, pp.110-118.
CN1CCC23C4C(=O)CCC2(C1CC5=C3C(=C(C=C5)O)O4)O Approved Mu opioid receptor , OPRK1 , OPRD1 Unknown, Kappa opioid receptor binding, delta opioid receptor binding
Hydrocodone Approved Mu opioid receptor , OPRK1 , OPRD1 Mu opioid receptor binding, Kappa opioid receptor binding, delta opioid receptor binding
CCCCCC1=CC(=C(C(=C1)O)C2=C(C=CC(=C2)C)C(=C)C)O Not approved Cannabinoid receptor , CB2 Disruption of circadian clock, Core clock modulation, Unknown, Cannabinoid receptor stimulation Lafaye G, Desterke C, Marulaz L, Benyamina A. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addiction Biology. 2018.
CCCCCC1=CC(=C(C(=C1)O)C2C=C(CCC2C(=C)C)C)O.CCCCCC1=CC(=C2C3C=C(CCC3C(OC2=C1)(C)C)C)O Not approved Cannabinoid receptor , CB2 Disruption of circadian clock, Core clock modulation, Unknown, Cannabinoid receptor stimulation Outen, J.D., Burhanullah, M.H., Vandrey, R., Amjad, H., Harper, D.G., Patrick, R.E., May, R.L., Agronin, M.E., Forester, B.P. and Rosenberg, P.B., 2021. Cannabinoids for agitation in Alzheimer's disease. American Journal of Geriatric Psychiatry, 29(12), pp.1253–1263
CN1CCC23C4C1CC5=C2C(=C(C=C5)O)OC3C(=O)CC4 Approved Mu opioid receptor , OPRK1 , OPRD1 Mu opioid receptor binding, Kappa opioid receptor binding, delta opioid receptor binding Shin, S.H., Lee, H.S., Kim, Y.S., Choi, Y.J., Kim, S.H., Kwon, H.C., Oh, S.Y., Kang, J.H., Sohn, C.H., Lee, S.M., Baek, J.H., Min, Y.J., Kim, C. and Chung, J.S., 2014. Clinical usefulness of hydromorphone-OROS in improving sleep disturbances in Korean cancer patients: a multicenter, prospective, open-label study. Cancer Research and Treatment, 46(4), pp.331–338.
CC1=CC(=CC(=C1)NC(=O)[C@@H]2CCCN2S(=O)(=O)C3=CC=C(C=C3)OC Not approved. orexin receptor subtypes (OX1 and OX2) Orexin Receptor Blockade Boss, C., Roch-Brisbare, C., Steiner, M.A., Treiber, A., Dietrich, H., Jenck, F., von Raumer, M., Sifferlen, T., Brotschi, C., Heidmann, B., Williams, J.T., Aissaoui, H., Siegrist, R. and Gatfield, J., 2014. Structure-activity relationship, biological, and pharmacological characterization of the proline sulfonamide ACT-462206: a potent, brain-penetrant dual orexin 1/orexin 2 receptor antagonist. ChemMedChem, 9(11), pp.2486–2496.
CCC(=O)C(CC(C)N(C)C)(C1=CC=CC=C1)C2=CC=CC=C2 Approved Mu opioid receptor , OPRK1 , OPRD1 , NMDA receptor , iGluRs Mu opioid receptor binding, Kappa opioid receptor binding, delta opioid receptor binding, opioid receptors binding Pačesová, D., Novotný, J. and Bendová, Z., 2016. The effect of chronic morphine or methadone exposure and withdrawal on clock gene expression in the rat suprachiasmatic nucleus and AA-NAT activity in the pineal gland. Physiological Research, 65(3), pp.517–525. , Pačesová, D., Spišská, V., Novotný, J. and Bendová, Z., 2023. Methadone administered to rat dams during pregnancy and lactation affects the circadian rhythms of their pups. Journal of Neuroscience Research, 101(11), pp.1737–1756.
CN(C)CC1CCCCC1(C2=CC(=CC=C2)OC)O Approved Mu opioid receptor , OPRK1 , OPRD1 Mu opioid receptor binding, Kappa opioid receptor binding, delta opioid receptor binding, opioid receptors binding Hakami, A.Y., Alghamdi, B.S. and Alshehri, F.S., 2024. Exploring the potential use of melatonin as a modulator of tramadol-induced rewarding effects in rats. Frontiers in Pharmacology, 15, p.1373746. , Liu, X.P. and Song, J.G., 2001. [Chronopharmacology of tramadol in mice]. Yao Xue Xue Bao (Acta Pharmaceutica Sinica), 36(8), pp.561–564.