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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
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.
CC(C)(C)C(C)(C1CC23CCC1(C4C25CCN(C3CC6=C5C(=C(C=C6)O)O4)CC7CC7)OC)O Approved Mu opioid receptor , OPRK1 , OPRD1 opioid receptors binding Pjrek, E., Frey, R., Naderi-Heiden, A., Strnad, A., Kowarik, A., Kasper, S. and Winkler, D., 2012. Actigraphic measurements in opioid detoxification with methadone or buprenorphine. Journal of Clinical Psychopharmacology, 32(1), pp.75–82 , Gauthier, E.A., Guzick, S.E., Brummett, C.M., Baghdoyan, H.A. and Lydic, R., 2011. Buprenorphine disrupts sleep and decreases adenosine concentrations in sleep-regulating brain regions of Sprague Dawley rat. Anesthesiology, 115(4), pp.743–753.
C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C.[Br-] Approved Muscarinic acetilcholine receptror M1 Affects melatonin synthesis Kärkelä, J., Vakkuri, O., Kaukinen, S., Huang, W.Q. and Pasanen, M., 2002. The influence of anaesthesia and surgery on the circadian rhythm of melatonin. Acta Anaesthesiologica Scandinavica, 46(1), pp.30–36. , Christensen, K.C., Stadil, F., Malmström, J. and Rehfeld, J.F., 1978. The effect of beta-adrenergic and cholinergic blockade on the circadian rhythm of gastrins in serum. Scandinavian Journal of Gastroenterology, 13(3), pp.263–272.
CN1CCC23C4C1CC5=C2C(=C(C=C5)OC)OC3C(C=C4)O Approved Mu opioid receptor opioid receptors binding Young, A.M., Thompson, T., Jensen, M.A. and Muchow, L.R., 1979. Effects of response-contingent clock stimuli on behavior maintained by intravenous codeine in the rhesus monkey. Pharmacology Biochemistry and Behavior, 11(1), pp.43–49. , Warfield, A.E., Prather, J.F. and Todd, W.D., 2021. Systems and circuits linking chronic pain and circadian rhythms. Frontiers in Neuroscience, 15, p.705173.
CN1CCC23C4C1CC5=C2C(=C(C=C5)O)OC3C(C=C4)O Approved Mu opioid receptor , OPRK1 , OPRD1 Unknown, opioid receptors binding Smyth, C., FitzGerald, R. and Waddington, J.L., 1995. Morphine phase-shifts circadian rhythms in mice: role of behavioural activation. Neuroreport, 7(1), pp.209–212.
CC(=O)OC1C=CC2C3CC4=C5C2(C1OC5=C(C=C4)OC(=O)C)CCN3C Not approved Mu opioid receptor , OPRK1 , OPRD1 opioid receptors binding Coffey, A.A., Guan, Z., Grigson, P.S. and Fang, J., 2016. Reversal of the sleep-wake cycle by heroin self-administration in rats. Brain Research Bulletin, 123, pp.33–46.
CC(CC1=CC=CC=C1)N Approved mPer2 , mPer1 , CLOCK-BMAL1 , Arntl (gene) Core clock modulation Wongchitrat, P., Mukda, S., Phansuwan-Pujito, P. and Govitrapong, P., 2013. Effect of amphetamine on the clock gene expression in rat striatum. Neuroscience Letters, 542, pp.126–130. , Khazaie, H., Ahmadi, H.R., Kiani, A. and Ghadami, M.R., 2019. Circadian melatonin profile in opium and amphetamine dependent patients: A preliminary study. Neurobiology of Sleep and Circadian Rhythms, 7, p.100046.
C(OC(C(F)(F)F)C(F)(F)F)F Approved mPer2 , mPer1 , CRY1-PER2 complex Core clock modulation, Unknown Kobayashi, K., Takemori, K. and Sakamoto, A., 2007. Circadian gene expression is suppressed during sevoflurane anesthesia and the suppression persists after awakening. Brain Research, 1185, pp.1–7. , Sugimura, S., Imai, R., Katoh, T., Makino, H., Hokamura, K., Kurita, T., Suzuki, Y., Aoki, Y., Kimura, T., Umemura, K. and Nakajima, Y., 2024. Effects of volatile anesthetics on circadian rhythm in mice: a comparative study of sevoflurane, desflurane, and isoflurane. Journal of Anesthesia, 38(1), pp.10–18.