Selegiline (l-deprenyl, Eldepryl) is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A. Dietary restrictions are common for MAOI treatments, but special dietary restrictions for lower doses have been found to be unnecessary, and dietary restrictions appear to be unnecessary at any dose when selegiline is taken as Emsam, the transdermal patch form, as no adverse events due to diet have ever been reported with Emsam. The drug was researched by Jozsef Knoll et al. (Hungary). Selegiline belongs to a class of drugs called phenethylamines. Selegiline consists of a l-desoxyephedrine (levomethamphetamine) skeleton with a propargyl group attached to the nitrogen atom.
Selegiline was discovered in Hungary in the 1960s. Joseph Knoll, a chair of pharmacology at the Semmelweis University in Budapest, was interested in the physiology of "drive" and the differences between high- and low-performing individuals. For his research, he required a molecule that combined amphetamine-like psychostimulant effect with a "psycho-energic" effect of monoamine oxidase inhibitors (MAOI). To do that, he decided to combine in the same molecule the structural features of the MAOI pargyline and the psychostimulant amphetamine. Knoll was a close friend of Meszaros, the research director of Chinoin, a Hungarian pharmaceutical company (later part of Sanofi). For this project, Meszaros put Knoll in contact with a chemist called Ecsery who worked in Chinoin in the field of phenethylamines. Escery made about 30 compounds, and Knoll selected the molecule of E-250 (deprenyl) based on its surprising properties. "The great discovery" (in Knoll's words) was that the new molecule did not increase blood pressure, unlike amphetamine, and moreover, it inhibited the blood pressure raising effect of amphetamine. The first publication on deprenyl in Hungarian appeared in 1964, followed by a paper in English in 1965. Deprenyl is a racemic compound, a mixture of two isomers called enantiomers. For the further pharmaceutical development, Knoll chose the (-)-enantiomer of deprenyl, which caused less hypermotility than the opposite (+)-enantiomer. This (-)-enantiomer (l-deprenyl, R-deprenyl) later has come to be called selegiline.
In 1971, Knoll showed that selegiline selectively inhibits the B-isoform of monoamine oxidase (MAO-B) and proposed that it is unlikely to cause the infamous "cheese effect" (hypertensive crisis resulting from consuming foods containing tyramine) that plagues non-selective MAO inhibitors. A few years later, two Parkinson's researchers based in Vienna, Peter Riederer and Walther Birkmayer, realized that selegiline could be useful in Parkinson's disease. One of their colleagues, Moussa Youdim, visited Knoll in Budapest and took selegiline from him to Vienna. In 1975, the Birkmayer's group published the first paper on the effect of selegiline in Parkinson's disease.
In 1967, a Hungarian psychiatrist Ervin Varga observed that racemic deprenyl given in large doses has an antidepressant action. This study was largely forgotten until the 2000s when Sommerset Pharmaceuticals developed selegiline patch for depression.
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