Nomifensine
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. 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. The drug was developed in the 1960s by Hoechst AG (now Sanofi-Aventis), 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. In January 1986 the drug was withdrawn by its manufacturers for safety reasons.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 (400–600 mg per day). In a 1989 study it was investigated for use in treating adult ADHD and proven effective. In a 1977 study it  has not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism. 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. 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 Nomifensine was subsequently withdrawn from the Canadian and UK markets as well. Some deaths were linked to immunohaemolytic anemia caused by this compound, although the mechanism remained unclear. In 2012 structure-affinity relationship data (compare SAR) were published. Synthesis. Nomifensine can be prepared from 2-nitro-"N"-methylbenzylamine (1) by reaction with phenacyl bromide (2) to give 3. Catalytic hydrogenation over Raney nickel to reduce nitro group, followed by reduction with sodium borohydride provides the alcohol 4. Sulfuric acid-catalyzed ring formation gives nomifensine