Aticaprant was originally developed byEli Lilly, was under development by Cerecor for a time, and is now under development byJanssen Pharmaceuticals.[2] As of July 2022, it is inphase IIIclinical trials for major depressive disorder.[2] In March 2025,Johnson & Johnson discontinued development of aticaprant for major depressive disorder due to lack of effectiveness in phase III trials.[5]
Aticaprant is apotent,selective, short-acting (i.e., non-"inactivating")antagonist of the KOR (Ki = 0.81 nM vs. 24.0 nM and 155 nM for theμ-opioid receptor (MOR) andδ-opioid receptor (DOR), respectively; approximately 30-fold selectivity for the KOR).[8][9][10] The drug has been found to dose-dependently blockfentanyl-inducedmiosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), suggesting that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less.[10] However, a more recent study assessing neuroendocrine effects of the drug in normal volunteers and subjects with a history of cocaine dependence reported observations consistent with modest MOR antagonism at the 10 mg dose.[11] Inanimal models ofdepression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such ascitalopram andimipramine.[12]
Positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that aticaprant is being explored at in clinical trials.[13][14] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[15][14] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[15][14] No seriousside effects were observed, and all side effects seen were mild to moderate and were not thought to be due to aticaprant.[14]
In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code CERC-501).[19]
In August 2017, it was announced that Cerecor had sold its rights to aticaprant toJanssen Pharmaceuticals.[22][21] Janssen was also experimenting withesketamine for the treatment of depression as of 2017.[21]
In March 2025,Johnson & Johnson discontinued development of aticaprant for major depressive disorder due to lack of effectiveness in phase 3 trials.[5] It has not completely discontinued aticaprant however and has said that it will continue to evaluate the drug in other areas.[5] A regulatory application for approval of the medication had previously been expected to be submitted by 2025.[2]
^abBrowne CA, Wulf H, Lucki I (2022). "Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder". In Liu-Chen LY, Inan S (eds.).The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 493–524.doi:10.1007/164_2020_432.ISBN978-3-030-89073-5.PMID33580854.S2CID231908782.
^abcReed B, Butelman ER, Kreek MJ (2022). "Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders". In Liu-Chen LY, Inan S (eds.).The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 473–491.doi:10.1007/164_2020_401.ISBN978-3-030-89073-5.PMID33174064.S2CID226305229.
^Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. (February 2014). "LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders".Neuropharmacology.77:131–144.doi:10.1016/j.neuropharm.2013.09.021.PMID24071566.S2CID3230414.
^Lowe SL, Wong CJ, Witcher J, Gonzales CR, Dickinson GL, Bell RL, et al. (September 2014). "Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects".Journal of Clinical Pharmacology.54 (9):968–978.doi:10.1002/jcph.286.PMID24619932.S2CID14814449.
^abUrbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor".Bioorganic & Medicinal Chemistry Letters.24 (9):2021–2032.doi:10.1016/j.bmcl.2014.03.040.PMID24690494.
^abPlaczek MS (August 2021). "Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography". In Liu-Chen LY, Inan S (eds.).The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 547–577.doi:10.1007/164_2021_498.ISBN978-3-030-89073-5.PMID34363128.S2CID236947969.
^Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, et al. (December 2011). "Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer".Journal of Medicinal Chemistry.54 (23):8000–8012.doi:10.1021/jm200789r.PMID21958337.
Helal MA, Habib ES, Chittiboyina AG (December 2017). "Selective kappa opioid antagonists for treatment of addiction, are we there yet?".European Journal of Medicinal Chemistry.141:632–647.doi:10.1016/j.ejmech.2017.10.012.PMID29107424.
McHugh KL, Kelly JP (2018). "Modulation of the central opioid system as an antidepressant target in rodent models".The Opioid System as the Interface between the Brain's Cognitive and Motivational Systems. Progress in Brain Research. Vol. 239. pp. 49–87.doi:10.1016/bs.pbr.2018.07.003.ISBN978-0-444-64167-0.PMID30314569.
Banks ML (2020). "The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research". In Nader MA, Hurd YL (eds.).Substance Use Disorders. Handbook of Experimental Pharmacology. Vol. 258. pp. 147–165.doi:10.1007/164_2019_268.ISBN978-3-030-33678-3.PMC7756963.PMID31463605.
