Mazindol, anorectic properties

The morpholine derivatives phenmetrazine (173 R = H) and phendimetrazine (173 R = Me) have stimulant properties like those of amphetamine. They have been used as anorectics, but they are liable to abuse. Another CNS stimulant used as an anorectic is mazindol (174), which bears some resemblance to certain benzhydrols with antidepressant activity. 

Mazindol is a tricyclic compound with central nervous system stimulant properties similar to those of amphetamine. It releases and blocks reuptake of dopamine and noradrenaline (1), and the actions of these catecholamines, not serotonin, are responsible for its anorectic activity. With fairly high doses (6 mg/day) central nervous system effects were reported in 30% of 23 patients (2). Euphoria does not occur at therapeutic doses, but can occur at higher doses. It has a much lower addiction potential than the amphetamines and practically no cases have been reported of a physical withdrawal syndrome. 

Compounds available in the United States are listed in Table 1. Whereas they vary in degree, all of them share similar liabilities of cardiovascular side effects, the potential for central nervous system (CNS) stimulation, the development of tolerance, and abuse potential. All, with the exception of mazindol, are derivatives of phenethylamine. The introduction of an oxygen atom on the p-carbon of the side chain tends to reduce CNS stimulant properties without decreasing the anorectic activity. Following the Federal Controlled Drug Act of 1970, drugs were classified into one of five schedules according to medical utility and abuse potential. 

There is a strong structural resemblance of (116a) to the anorectic compound mazindol (117). This resemblance is also found in the NA-uptake inhibiting properties (117) is a potent blocker of NA-accumulation of the rat heart in vivo [301]. Compound (118), obtained by protonation of (117), is an even more potent NA uptake inhibitor, and also shows strong DA and 5-HT uptake blocking properties in vitro [106]. 

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