Selegiline 14611-51-9

History

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" 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.

Uses

The main use of selegiline is in the treatment of Parkinson's disease. It can be used on its own or in a combination with another agent, most often L-DOPA. For the newly diagnosed Parkinson's patients, selegiline appears to slow the progression of the disease. It delays the time point when the L-DOPA (levodopa) treatment becomes necessary from 10-12 to 18 months. The idea behind adding selegiline to levodopa is to decrease the dose of levodopa and thus reduce the motor complications of levodopa therapy. Comparisons of patients on levodopa + placebo vs levodopa + selegiline showed that selegiline allowed reduction of the levodopa dose by about 40%. Selegiline + levodopa also extended the time until the levodopa dose had to be increased from 2. 6 to 4. 9 years. Selegiline is also used (at extremely high dosages relative to humans) in veterinary medicine to treat the symptoms of Cushing's disease and cognitive dysfunction in dogs. As of June 26, 2006, a selegiline transdermal patch is being tested for its effectiveness in treating ADHD. Several clinical studies are currently underway to evaluate selegiline's effectiveness in helping people stop smoking tobacco or marijuana.

Side effects

Due to the primary metabolites of L-amphetamine and L-methamphetamine, Selegiline shares many side effects seen with these sympathomimetic stimulants. Minor side effects such as dizziness, dry mouth, difficulty falling or staying asleep, muscle pain, rash, nausea and constipation have been seen. More serious side effects such as severe headache, tachycardia, arrhythmia, hallucinations, chorea, or difficulty breathing should be investigated by health professionals immediately.

Pharmacology

Pharmacokinetics

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please add citations detailing bioavailability

date=June 2008