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Nomifensine
Systematic (IUPAC) name
(RS)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-8-amine
Identifiers
CAS number 24526-64-5
ATC code N06AX04
PubChem 4528
Chemical data
Formula C 16H18N2  
Mol. mass 238.328
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

Nomifensine maleate (Merital) is a norepinephrine-dopamine reuptake inhibitor[1] test-marketed in the United States by Hoechst AG (now Sanofi-Aventis) that increases the amount of synaptic dopamine available to receptors by blocking dopamine's re-uptake transporter. This is a mechanism of action shared by some recreational drugs like cocaine (see DRI).

Merital was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50-225mg per day, both motivating and anxiolytic. There were relatively few adverse effects (mainly dry mouth, headache, nausea), the drug was not sedating, 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.

Later studies in the 1980s concluded that there was potential for dependence and abuse of nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400-600mg per day). Nomifensine is now only rarely used as an antidepressant due to concerns about causing haemolytic anaemia, and problems with overstimulation and hyperthermia in overdose. It has been investigated for use in treating ADHD and animal models of Parkinson's disease with some success. However, it has not proved of benefit to human patients suffering from advanced Parkinsonism.[2][3][4]

Nomifensine was withdrawn from mainstream medical use for a variety of reasons, abuse potential being a concern, but also problems with kidney and liver toxicity and haemolytic anaemia were cited, and some deaths were linked to the use of this compound although the mechanism remains unclear. A likely cause of nomifensine toxicity is the anilino group, as compounds containing this chemical substructure are notorious for producing toxic metabolites.[5]

Nomifensine is now mainly used in scientific research, particularly in studies involving dopamine release in response to addiction. This is because typically different areas of the brain have different amounts of dopamine transporter, but when Nomifensine is administered, a sufficient basal dopamine level is reached to allow comparison of dopamine release from drugs of abuse in different areas of the brain without the results being skewed by re-uptake speed variation.

The dihydroxylated analog of nomifensine is an interested analog that is known to have been reported.[6] (see also)[7]

Hexahydro-1H-indeno[1,2-b]pyridines

Anybody that is interested in nomifensine will be interested in learning about the related compounds of the present section.[8][9][10]

Kunstmann.png

References

  1. ^ Nomifensine: A review of its pharmacological prope...[Drugs. 1979] - PubMed Result
  2. ^ Shekim WO, Masterson A, Cantrell DP, Hanna GL, McCracken JT. Nomifensine maleate in adult attention deficit disorder. J Nerv Ment Dis. 1989 May;177(5):296-9.
  3. ^ McKinley ET, Baranowski TC, Blavo DO, Cato C, Doan TN, Rubinstein AL. Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons. Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons.Brain Res Mol Brain Res. 2005 Nov 30;141(2):128-37. PMID 16209898
  4. ^ Bedard P, Parkes JD, Marsden CD. Nomifensine in Parkinson's disease. Br J Clin Pharmacol. 1977;4Suppl 2:187S-190S. PMID 334223
  5. ^ Galbaud du Fort G. Hematologic toxicity of antidepressive agents. (French). L'Encephale. 1988 Jul-Aug;14(4):307-18.
  6. ^ Dandridge PA, Kaiser C, Brenner M, Gaitanopoulos D, Davis LD, Webb RL, Foley JJ, Sarau HM. Synthesis, resolution, absolute stereochemistry, and enantioselectivity of 3',4'-dihydroxynomifensine. J Med Chem. 1984 Jan;27(1):28-35. PMID 6317860
  7. ^ Kaiser C, Dandridge PA, Garvey E, Hahn RA, Sarau HM, Setler PE, Bass LS, Clardy J. Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine. J Med Chem. 1982 Jun;25(6):697-703. PMID 6980283
  8. ^ Kunstmann R, Gerhards H, Kruse H, Leven M, Paulus EF, Schacht U, Schmitt K, Witte PU. Resolution, absolute stereochemistry, and enantioselective activity of nomifensine and hexahydro-1H-indeno[1,2-b]pyridines. J Med Chem. 1987 May;30(5):798-804. PMID 3572969
  9. ^ Kunstmann R, Fischer G. Molecular analysis of hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants. J Med Chem. 1984 Oct;27(10):1312-6. PMID 6481767
  10. ^ Kunstmann R, Lerch U, Gerhards H, Leven M, Schacht U. 2,3,4,4a,5,9b-Hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants. J Med Chem. 1984 Apr;27(4):432-9. PMID 6708046







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