Selegiline

The cascade of apoptosis may be promoted by mitogen activated protein (MAP) kinase activation. CEP1347, a small molecule MAP kinase inhibitor that crosses the blood brain barrier is protective in MPTP-treated mice (Saporito et al., 1999). A clinical trial showed good tolerability, no interference with L-dopa pharmacokinetics, and no symptomatic effects of treatment over a 4-week period (Parkinson Study Group, 2004). A larger phase II trial has commenced. 

Another proposed mechanism of neuronal death is oxidative stress due to the accumulation of free radicals. Normal and abnormal cellular metabolic processes involving molecular oxygen produce free radicals, which can cause oxidative damage to lipids, proteins and nucleic acids (Andersen, 2004). 

Alpha tocopherol (vitamin E), a naturally occurring antioxidant, delays disease onset in SODl transgenic mice (Gurney et al., 1996). One epidemiological study suggested that regular intake of vitamin E may reduce the risk of contracting ALS (Ascherio et al., 2005). A randomized, placebo controlled trial of vitamin E 500 mg twice daily showed 

Selegiline may have anti-oxidant and anti-apoptotic properties in addition to inhibiting MAO, and has been reported to increase SOD activity in the basal ganglia of rats (Knoll, 1989). There have been several duals of selegiline 10mg per day in patients with ALS a randomized, placebo controlled, double blind trial (Lange et al., 1998), and a placebo-con trolled crossover trial (Mitchell et al., 1995). Neither showed improvement in functional or subjective rating scales, but both trials were underpowered due to insufficient sample size and so may be considered inconclusive. 

Chemicai Neme N-(1-Phenvlisopropvl)-N-methvl-prop-2-vnvlamine Common Name Deprenil, deprenaline 

50 g of L-N-(2-phenylisopropyl)methylamine are dissolved in 62.5 ml of toluene, whereupon 13 ml of propargyl bromide are added dropwise within about 20 minutes at a temperature in the range of 50°C to 60°C. The reaction mixture is stirred at 80°C for 3 hours, whereupon it is cooled and the toluene solution is extracted with 125 ml of a 5% hydrochloric acid solution. The acidic layer is separated and made alkaline. The precipitated oil is isolated, washed with benzene and evaporated. The residue is subjected to fractional distillation in vacuo. L-N-(2-phenylisopropyl)methylamine distills off at 65°C to 67°C (0.6 mm Hg, n = 1.5083). The L-N-(1-phenylisopropyll-N-methyl-prop-2-ynylamlne is obtained at92°C to 93°C (0.8 mm Hg, n = 1.51801. The melting point of the hydrochloride is 141°C. 

Chinoin Gyogyszer- es Vegyeszeti Termekek Gyara R.T. British Patents 1,031,425 June 2, 1966 and 1,153,578 May 29, 1969 

Chemical Name N-(1-Phenylisopropyl)-N-methyl-prop-2-ynylamine Common Name Deprenil,deprenaline 

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A large number of molecules have provided experimental evidence of neuroprotection in in vitro and in vivo models of Parkinson s disease and many of these putative neuroprotective substances are now the objects of clinical trials. Recently, a team of experts has identified potential neuroprotective agents to be tested in pilot studies [4]. Twelve compounds have been considered for clinical trials caffeine, coenzyme Q 10, creatine, estrogen, GPI1485, GM-1 ganglioside, minocycline, nicotine, pramipexole, ropinirol, rasagiline, and selegiline (for individual discussion see [4]). 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

Monoamine Oxidases and their Inhibitors. Figure 2 Structures of MAO inhibitors. In the top row, the structural similarity between selegiline/L-deprenyl and methamphetamine is shown. Below are the aminoindan series of propargylamine compounds such as rasagiline. Next, the bifunctional MAO and cholinesterase inhibitors (ladostigil) and lastly, the iron chelator-MAO inhibitors. 

Sano M, Ernesto C, Thomas RG et al (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer s disease. The Alzheimer s Disease Cooperative Study. N Engl JMed 336 1216-1222... 

The mechanism of action of amantadine (Symmetrel) and selegiline (Eldepryl) in die treatment of parkinsonism is not fully understood. 

The most common serious adverse reactions to amantadine are orthostatic hypotension, depression, congestive heart failure, psychosis, urinary retention, convulsions, leukopenia, and neutropenia Less serious reactions include hallucinations, confusion, anxiety, anorexia, nausea, and constipation. Adverse reactions with selegiline include nausea, hallucinations, confusion, depression, loss of balance, and dizziness. 

C14H21NO, 93777-08-3) see Selegiline methanesulfochloride see under mesyl chloride methanesulfonanilide... 

CjHjBr 106-96- 7) see. Haloprogin Pargyline Parsalmide Pinazepam Selegiline... 

More than 40 medications have been investigated but none have shown consistent efficacy for primary cocaine or amphetamine dependence. These medications include dopaminergic agonists, antidepressants, and more recently disulfiram, selegiline, and a cocaine vaccine (see Table 5—2 for summary). Studies have been relatively brief and have focused on abstinence initiation rather than on relapse prevention, but even these modest treatment goals have not been attained. The focus in the discussion that follows is on pharmacotherapies for cocaine dependence, because very few clinical trials have been completed with amphetamine-dependent patients. Furthermore, none of the studies of amphetamine dependence have shown results different from those described for cocaine dependence (Rawson et al. 2002b Srisurapanont et al. 2001). 

Amantidine, bromocriptine, mazindol, pergolide, cabergoline, L-dopa/carbidopa, pramipexole, ABT-431, catecholamine metabolism inhibitors (disulfiram, phenelzine, selegiline), amineptine Methylphenidate, /-amphetamine, tropanes, GBR-12909 (partial agonist that may also act as antagonist), modafinil, coca tea... 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

ENTACAPONE CARBI[X>PA SELEGILINE TOLCAPONE BENSERAZIDE [Pg.306]

The deamination of DA to DOPAC can be prevented by MAOb inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD — dopa decarboxylase MAO—monoamine oxidase COMT—catechol-o-methyl transferase... 

There have been few attempts to manipulate the monoamines in AzD and those using selegiline, the MOAb inhibitor, have shown little effect although the 5-HT3 antagonist, ondansetron, may give a slight improvement. 

Yavich, L, Sirvio, J, Haapalinna, A, Puumala, T, Koivisto, E, Heinonen, E and Reikkinen, PJ (1996) The systemic administration of tacrine or selegiline facilitate spatial learning in aged Fisher 344 rats. J. Neural Trans. 103 619-626. 

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