Nomifensine Explained

Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor, i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters.[1] This is a mechanism of action shared by some recreational drugs like cocaine and the medication tametraline (see DRI). Research showed that the (S)-isomer is responsible for activity.[2]

The drug was developed in the 1960s by Hoechst AG (now Sanofi-Aventis),[3] who then test marketed it in the United States. It was an effective antidepressant, without sedative effects. Nomifensine did not interact significantly with alcohol and lacked anticholinergic effects. No withdrawal symptoms were seen after 6 months treatment. The drug was however considered not suitable for agitated patients as it presumably made agitation worse.[4] [5] In January 1986 the drug was withdrawn by its manufacturers for safety reasons.[6]

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).[7]

In a 1989 study it was investigated for use in treating adult ADHD and proven effective.[8] In a 1977 study it was not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.[9]

Clinical uses

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.

Side effects and withdrawal from market

During treatment with nomifensine there were relatively few adverse effects, mainly renal failure, paranoid symptoms, drowsiness or insomnia, headache, and dry mouth. Side effects affecting the cardiovascular system included tachycardia and palpitations, but nomifensine was significantly less cardiotoxic than the standard tricyclic antidepressants.[10]

Due to a risk of haemolytic 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 Nomifensine was subsequently withdrawn from the Canadian and UK markets as well.[11] Some deaths were linked to immunohaemolytic anemia caused by this compound, although the mechanism remained unclear.[12]

In 2012 structure-affinity relationship data (compare SAR) were published.[13]

Synthesis

Note that nomifensine was a Progenitor to Gastrophenazine. See also: Isatin derivatives.[14]

The alkylation between N-methyl-2-nitrobenzylamine [56222-08-3] (1) and phenacyl bromide (2) gives CID:15326127 (3). Catalytic hydrogenation over Raney Nickel reduces the nitro group to give CID:15113381 (4). The reduction of the ketone group with sodium borohydride to alcohol gives [65514-97-8] (5). Acid catalysed ring closure completes the formation of nomifensine (6).

See also

Notes and References

  1. Brogden RN, Heel RC, Speight TM, Avery GS . Nomifensine: A review of its pharmacological properties and therapeutic efficacy in depressive illness . Drugs . 18 . 1 . 1–24 . July 1979 . 477572 . 10.2165/00003495-197918010-00001 . 23952170 .
  2. 'Chirality and Biological Activity of Drugs' page 138
  3. US . patent . 3577424 . 4-Phenyl-8-Amino Tetrahydroisoquinolines . Farbwerke Hoechst . 1971-05-04 . Ehrhart . Gustav. Schmitt . Karl. Hoffmann . Irmgard. Ott . Heinrich.
  4. Habermann W . A review of controlled studies with nomifensine, performed outside the UK . British Journal of Clinical Pharmacology . 4Suppl 2 . Suppl 2 . 237S–241S . 1977 . 334230 . 1429098 . 10.1111/j.1365-2125.1977.tb05759.x .
  5. Yakabow AL, Hardiman S, Nash RJ . 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 . April 1984 . 6370985 .
  6. CSM Update: Withdrawal of nomifensine . British Medical Journal . 293 . 6538 . 41 . July 1986 . 20742679 . 1340782 . 10.1136/bmj.293.6538.41 .
  7. Böning J, Fuchs G . Nomifensine and psychological dependence--a case report . Pharmacopsychiatry . 19 . 5 . 386–8 . September 1986 . 3774872 . 10.1055/s-2007-1017275 . 29192368 .
  8. Shekim WO, Masterson A, Cantwell DP, Hanna GL, McCracken JT . Nomifensine maleate in adult attention deficit disorder . The Journal of Nervous and Mental Disease . 177 . 5 . 296–9 . May 1989 . 2651559 . 10.1097/00005053-198905000-00008 . 1932119 .
  9. Bedard P, Parkes JD, Marsden CD . Nomifensine in Parkinson's disease . British Journal of Clinical Pharmacology . 4Suppl 2 . Suppl 2 . 187S–190S . 1977 . 334223 . 1429119 . 10.1111/j.1365-2125.1977.tb05751.x .
  10. Hanks GW . A profile of nomifensine . British Journal of Clinical Pharmacology . 4Suppl 2 . 243S–248S . 1977 . Suppl 2 . 911653 . 1429121 . 10.1111/j.1365-2125.1977.tb05760.x .
  11. Web site: Nomifensine DB04821 . Drugbank.ca .
  12. Galbaud du Fort G . [Hematologic toxicity of antidepressive agents] . fr . L'Encéphale . 14 . 4 . 307–18 . 1988 . 3058454 . Hematologic Toxicity of Antidepressive Agents .
  13. Pechulis AD, Beck JP, Curry MA, Wolf MA, Harms AE, Xi N, Opalka C, Sweet MP, Yang Z, Vellekoop AS, Klos AM, Crocker PJ, Hassler C, Laws M, Kitchen DB, Smith MA, Olson RE, Liu S, Molino BF . 6 . 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors . Bioorganic & Medicinal Chemistry Letters . 22 . 23 . 7219–22 . December 2012 . 23084899 . 10.1016/j.bmcl.2012.09.050 .
  14. DE3333994 idem Karl-Heinz Boltze, et al. (1986 to TROPONWERKE & Co KG A CORP OF GERMANY GmbH, Troponwerke GmbH).
  15. 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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