Nomifensine

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Nomifensine
Systematic (IUPAC) name
(±)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-8-amine
Identifiers
CAS number 24526-64-5
ATC code N06AX04
PubChem 4528
DrugBank DB04821
Chemical data
Formula C16H18N2 
Mol. mass 238.328 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life 1.5-4 hours
Excretion Kidney (88%) within 24 hours[1]
Therapeutic considerations
Pregnancy cat.

?

Legal status

Prescription only

Routes Oral

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor developed by a team at Hoechst AG in the 1960s.[2] The drug was test marketed in the United States by Hoechst AG (now Sanofi-Aventis), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters.[3] 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.[4] The drug 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.[5][6] In January 1986 the drug was withdraw 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 has been investigated for use in treating adult ADHD and proven successful.[9] In a 1977 study it has not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.[10]

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

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 triciclyc antidepressants.[11]

Due to the risk of a risk of haemolytic anaemia, the U.S. Food and Drug Administration (FDA) withdrew approval for nomifensine on March 20, 1992. Nomifensine has subsequently been 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]

In 2012 structure–affinity relationship data (compare SAR) were published.[14]

Synthesis

Nomifensine synthesis:[15]

See also


References

  1. Heptner W, Hornke I, Uihlein M (April 1984). "Kinetics and metabolism of nomifensine". The Journal of Clinical Psychiatry. 45 (4 Pt 2): 21–5. PMID 6370971. 
  2. {{{1}}} patent {{{2}}}
  3. PMID 477572 (PubMed)
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  4. 'Chirality and Biological Activity of Drugs' page 138
  5. PMID 334230 (334230 &dopt=Abstract PubMed)
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  6. PMID 6370985 (&dopt=Abstract PubMed)
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  7. "CSM Update: Withdrawal of nomifensine". British Medical Journal (Clinical Research Ed.). 293 (6538): 41. July 1986. PMC 1340782Freely accessible. PMID 20742679. doi:10.1136/bmj.293.6538.41. 
  8. PMID 3774872 (PubMed)
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  9. PMID 2651559 (PubMed)
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  10. PMID 334223 (PubMed)
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  11. Hanks GW (1977). "A profile of nomifensine". British Journal of Clinical Pharmacology. 4Suppl 2: 243S–248S. PMC 1429121Freely accessible. PMID 911653. 
  12. "Nomifensine DB04821". Drugbank.ca. 
  13. PMID 3058454 (PubMed)
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  14. Pechulis AD et al (2012): "4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors", Bioorg. Med. Chem. Lett., 7219. PMID 23084899
  15. Template:Cite doi



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