Nomifensine was considered an effectiveantidepressant that lacked sedative effects. It did not interact significantly withalcohol and lackedanticholinergic effects. Nowithdrawal symptoms were seen after 6 months treatment. The drug was, however, considered not suitable for agitated patients as it presumably made agitation worse.[5][6] In January 1986 the drug was withdrawn by its manufacturers for safety reasons.[7]
Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).[8]
In a 1989 study it was investigated for use in treatingattention deficit hyperactivity disorder (ADHD) in adults and was proven to be effective.[9] In a 1977 study it was not proven of benefit in advancedparkinsonism, except for depression associated with the parkinsonism.[10]
Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic.
During treatment with nomifensine there were relatively few adverse effects, mainlyrenal failure, paranoid symptoms,drowsiness orinsomnia,headache, anddry mouth. Side effects affecting the cardiovascular system includedtachycardia andpalpitations, but nomifensine was significantly less cardiotoxic than the standard tricyclic antidepressants.[11]
Due to a risk ofhaemolytic anaemia, the U.S.Food and Drug Administration (FDA) withdrew approval for nomifensine on March 20, 1992. Nomifensine was subsequently withdrawn from the Canadian and UK markets as well.[12] Some deaths were linked to immunohaemolytic anemia caused by this compound, although the mechanism remained unclear.[13]
The alkylation between N-methyl-2-nitrobenzylamine [56222-08-3] (1) andphenacyl bromide (2) givesCID:15326127 (3).Catalytic hydrogenation over Raney Nickel reduces the nitro group to giveCID:15113381 (4). The reduction of the ketone group withsodium borohydride to alcohol gives [65514-97-8] (5). Acid catalysed ring closure completes the formation of nomifensine (6).
^Heptner W, Hornke I, Uihlein M (April 1984). "Kinetics and metabolism of nomifensine".The Journal of Clinical Psychiatry.45 (4 Pt 2):21–5.PMID6370971.
^Brogden RN, Heel RC, Speight TM, Avery GS (July 1979). "Nomifensine: A review of its pharmacological properties and therapeutic efficacy in depressive illness".Drugs.18 (1):1–24.doi:10.2165/00003495-197918010-00001.PMID477572.S2CID23952170.
^US patent 3577424, Ehrhart G, Schmitt K, Hoffmann I, Ott H, "4-Phenyl-8-Amino Tetrahydroisoquinolines", issued 1971-05-04, assigned to Farbwerke Hoechst
^Yakabow AL, Hardiman S, Nash RJ (April 1984). "An overview of side effects and long-term experience with nomifensine from United States clinical trials".The Journal of Clinical Psychiatry.45 (4 Pt 2):96–101.PMID6370985.
^Shekim WO, Masterson A, Cantwell DP, Hanna GL, McCracken JT (May 1989). "Nomifensine maleate in adult attention deficit disorder".The Journal of Nervous and Mental Disease.177 (5):296–9.doi:10.1097/00005053-198905000-00008.PMID2651559.S2CID1932119.
^Galbaud du Fort G (1988). "[Hematologic toxicity of antidepressive agents]" [Hematologic Toxicity of Antidepressive Agents].L'Encéphale (in French).14 (4):307–18.PMID3058454.
^abZára-Kaczián E, György L, Deák G, Seregi A, Dóda M (July 1986). "Synthesis and pharmacological evaluation of some new tetrahydroisoquinoline derivatives inhibiting dopamine uptake and/or possessing a dopaminomimetic property".Journal of Medicinal Chemistry.29 (7):1189–95.doi:10.1021/jm00157a012.PMID3806569.
^DE 3333994, Boltze KH, Davies MA, Junge B, Schuurman T, Traber J, "Pyridoindole derivatives, compositions and use", issued 14 January 1986, assigned to Troponwerke GmbH
^Hoffmann I, Ehrhart G, Schmitt K (July 1971). "[8-amino-4-phenyl-1,2,3,4-tetrahydroisoquinolines, a new group of antidepressive psycholeptic drugs]".Arzneimittel-Forschung.21 (7): 1045.PMID5109496.
^Ulin J, Gee AD, Malmborg P, Tedroff J, Långström B (1989). "Synthesis of racemic (+) and (-) N-[methyl-11C]nomifensine, a ligand for evaluation of monoamine re-uptake sites by use of positron emission tomography".International Journal of Radiation Applications and Instrumentation, Part A.40 (2):171–6.doi:10.1016/0883-2889(89)90194-9.PMID2541106.
^Ivanov TB, Mondeshka DM, Angelova IG (1989). "Verbesserte Synthese von 8-Amino-2-methyl-4-phenyl-1, 2, 3, 4-Tetrahydroisochinolin".Journal für Praktische Chemie.331 (5): m 731–735.doi:10.1002/prac.19893310505.
^Venkov AP, Vodenicharov DM (1990). "A New Synthesis of 1, 2, 3, 4-Tetrahydro-2-methyl-4-phenylisoquinolines".Synthesis.1990 (3):253–255.doi:10.1055/s-1990-26846.
^Pechulis AD, Beck JP, Curry MA, Wolf MA, Harms AE, Xi N, et al. (December 2012). "4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors".Bioorganic & Medicinal Chemistry Letters.22 (23):7219–22.doi:10.1016/j.bmcl.2012.09.050.PMID23084899.
^Kunstmann R, Gerhards H, Kruse H, Leven M, Paulus EF, Schacht U, et al. (May 1987). "Resolution, absolute stereochemistry, and enantioselective activity of nomifensine and hexahydro-1H-indeno[1,2-b]pyridines".Journal of Medicinal Chemistry.30 (5):798–804.doi:10.1021/jm00388a009.PMID3572969.
^abSalamone JD, Correa M (January 2024). "The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine".Annu Rev Psychol.75:1–32.doi:10.1146/annurev-psych-020223-012208.hdl:10234/207207.PMID37788571.
^Nishino S, Kotorii N (2016). "Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics".Narcolepsy. Cham: Springer International Publishing. pp. 307–329.doi:10.1007/978-3-319-23739-8_22.ISBN978-3-319-23738-1.
^Nishino S (2007). "Narcolepsy: pathophysiology and pharmacology".J Clin Psychiatry.68 (Suppl 13):9–15.PMID18078360.
^Nishino S, Mao J, Sampathkumaran R, Shelton J (1998). "Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants".Sleep Res Online.1 (1):49–61.PMID11382857.
^Jellinger K, Koeppen D, Rössner M. Langzeitbehandlung depressiver Syndrome mit Psyton [Long-term treatment of depressive syndromes with Psyton (author's transl)]. Wien Med Wochenschr. 1982 Apr 30;132(8):183-8. German. PMID 6125057.
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