Nomifensine

Most of the widely used antidepressants are tricyclics related to imipramine. A 1-phenyltetrahy-droisoquinoline analogue, nomifensine (60), departs from this structural pattern. Hiarmacologi-cally it inhibits the reuptake of catecholamines such as dopamine at neurons. It can be synthesized by alkylation of 2-nitrobenzyl-methylamine with phenacyl bromide followed by catalytic reduction of the nitro group (Pd-C) and then hydride reduction of the keto moiety to give 59. Strong acid treatment leads to cyclodehydration to nomifensine (60) [17]. 

Timolol maleate a-Bromoacetophenone Nomifensine maleate Bromoacetyl bromide Bromazepam Cephapirin sodium Clonazepam Flunitrazepam 5-Bromoacetyl salicylamide Labetalol HCI m-Bromoanisole Tramadol HCI p-Bromoanisole Cyclofenil Bromobenzene... 

C8H7B1O 70-11-1) see Fendosal Hexocyclium metilsulfate Levamisole Nomifensine 4 -bromoacetophenone (CjH7BrO 99-90-1) see Zimeldine bromoacetyl bromide... 

C],jH2(iN20 65514-97-8) see Nomifensine At-methyl-N-(2-aminobenzyl)phenacylamine (CitHisNjO 119810-30-9) see Nomifensine 4-(methylamino)butanoic acid hydrochloride (C5H,2C1N02 6976-17-6) see Azelastine methyl 3-amino-2-butenoate... 

C H,, N203 85660-33-9) see Nomifensine 7V-methyl-lV-(2-nitrobenzyl)phenacylamine (C (,H 9N203 102436-67-9) see Nomifensine 2-methyl-5-nitro-4,6-dihydroxypyrimidine (C5H5N3O4 53925-27-2) see Moxonidine 2-methyl-5-nitroimidazole... 

While Funk et al. did not use temperatures above 30 °C during the irradiation times discussed above, Sistovaris combined UV irradiation with simultaneous heating (70 °C, 2 h) of the TLC layers [24]. After this treatment nomifensine and its metabolites appeared as intense yellow fluorescent ehromatogram zones on a dark background. 

Nomifensine and metabolites 70°C, 2 h + UV2S4 Heating and simultaneous UV irradiation produced intense yellow fluorescence (Xn > 460 nm, cut off filter). [30]... 

The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity. Thus DA terminals will not concentrate NA and the DA transporter is blocked by a drug such as nomifensine which has less effect on NA uptake. Despite this selectivity some compounds, e.g. amphetamine and 6-OHDA (but not MPTP), can be taken up by both neurons. The role of blocking DA uptake in the central actions of cocaine and amphetamine is considered later (Chapter 23). 

Dubocovich, M.L. and Zahniser, N.R., Binding characteristics of dopamine uptake inhibitor [3H]nomifensine to striatal membranes, Biochem. Pharmacol., 34, 1137, 1985. 

Carboni, E., Imperato, A., Perezzani, L., and Di Chiara, G., Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accum-bens of freely moving rats, Neuroscience, 28, 653, 1989. 

In contrast to a-methyldopa-induced hemolytic anemia, most drug-induced hemolytic anemia, especially for penicillins [34] and cephalosporins [35], involves drug-dependent antibodies, presumably because the drug acts as a hapten to directly modify erythrocytes or form immune complexes [36], However, there are many examples where a drug, such as nomifensine, induces both drug- (or metabolite)-dependent and drug-... 

Salama, A. and Mueller-Eckhardt, C., Rh blood group-specific antibodies in immune hemolytic anemia induced by nomifensine, Blood, 68,1285, 1986. 

Granier F, Girard M, Schmitt L, Boscredon J, Oules J, Escande M. (1985). Depression and anxiety mianserin and nomifensine compared in a double-blind multicentre trial. Acta Psychiatr Scand, 320(suppl) 67-74. 

Stanford JA, Currier TD, Purdom MS, Gerhardt GA. 2001. Nomifensine reveals age-related changes in K(+)-evoked striatal DA overflow in F344 rats. Neurobiol Aging 22(3) 495-502. 

With regard to the specific action of antidepressants on the dopaminergic system, there is evidence that buproprion (not marketed in most countries in Western Europe as an antidepressant but available in North America), amineptine and nomifensin (withdrawn because of the rare occurrence of haemolysis) owed their antidepressant efficacy to their ability to increase central dopaminergic function. There are also open label studies to suggest... 

Lastly, nomifensine was an interesting antidepressant that also had noradrenaline, dopamine and, due to its 4-hydroxy metabolite, serotonin reuptake properties. It was withdrawn some years ago because of the occurrence of haemolytic anaemia in a small number of patients. It was a particularly effective drug in the treatment of depression in patients with epilepsy as, unlike many antidepressants available at that time, it did not affect the seizure threshold. 

---