Nomifensine
Nomifensine, formerly sold under the brand names Merital and Alival, is a norepinephrine–dopamine reuptake inhibitor drug that was developed in the 1960s by Hoechst AG, who then test marketed it in the United States.
Nomifensine was considered an effective antidepressant that lacked sedative effects. It 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. In January 1986 the drug was withdrawn by its manufacturers for safety reasons.
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.
In a 1989 study it was investigated for use in treating attention deficit hyperactivity disorder in adults and was proven to be effective. In a 1977 study it was not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.
Medical 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.Adverse 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 tricyclic antidepressants.Withdrawal from market
Due to a risk of haemolytic anaemia, the U.S. Food and Drug Administration withdrew approval for nomifensine on March 20, 1992. Nomifensine was subsequently withdrawn from the Canadian and UK markets as well. Some deaths were linked to immunohaemolytic anemia caused by this compound, although the mechanism remained unclear.Synthesis
Nomifensine was a progenitor to Gastrophenzine. See also: Isatin derivatives.File:Nomifensine synthesis.svg|class=skin-invert-image|thumb|500px|center| Synthesis:
Radiolabelled:; Improved method:; Analogs: Enantiomers:
The alkylation between N-methyl-2-nitrobenzylamine and phenacyl bromide gives . Catalytic hydrogenation over Raney Nickel reduces the nitro group to give . The reduction of the ketone group with sodium borohydride to alcohol gives . Acid catalysed ring closure completes the formation of nomifensine.