If I were a lab rat on Selegiline I would be most Irie!  :)

This is just a quick and dirty -- clumsy unedited
conversion from a PDF file to a standard text file.
IU trust those of you that can read and understand it will
overlook the errors in the conversion and savor the contents
and what they relate.  
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The Structure and Activity of Selegiline, its
Functional Groups, and Congeners

Figure 1: Selegiline (l-deprenyl), N-propargyl levo-methamphetamine
Orbitals are for mathematicians Ð
Organic chemistry is for people who like to cook!
Ð Alexander Shulgin
1

Selegiline, or l-deprenyl, was first synthesized in 1962 by Joseph Knoll. It is a
very close derivative of l-methamphetamine 1), identical but for the addition of a
propargyl group to its single nitrogen atom. l-Methamphetamine is itself one of the
many derivatives of phenethylamine 2, the foundation for a great number of com-pounds
of psychopharmacological interest [19]. While selegiline does inherit some
of the pharmacological actions characteristic of phenethylamines, the addition of
the rather innocuous-looking propargylamine group compounds and complements
those with its own, truly surprising, dimension of activity.
NH 2
Figure 2: PEA, Phenethylamine
H 2 N
Figure 3: PAA, Propargylamine
1 Pharmacological Activity of Propargylamines
The monoamine oxidase enzymes, types A and B, are the bodyÕs primary means
of deactivating amines, or compounds derived from ammonia by replacing one
or more of its hydrogen atoms with hydrocarbon groups. Though both enzymes
catalyse the oxidation reaction with amines resulting in the production of ammo-nia
and hydrogen peroxide shown in equation 1, they may be characterized by the
compounds (or ÒsubstratesÓ) they work on, as well as by the compounds which
inhibit their activity. While MAO-A preferentially deaminates serotonin and nora-drenaline
and is selectively inhibited by clorgyline, MAO-B tends to catalyse the
reduction of dopamine and -phenethylamine and may be inhibited by aliphatic
propargylamines like selegiline [5].
RCH2NH2 + H2O + O2 -> RCHO + NH3 + H2O2 (1)
As a selective and irreversible inhibitor of MAO-B, selegiline prevents the
deamination of dopamine and -phenethylamine, thus increasing the concentra-tion
of those monoamines while restricting the production of hydrogen peroxide,
a pro-oxidant or Òreactive oxygen speciesÓ (ROS). By increasing dopamine lev-els,
selegiline forestalls and decreases by 30Ð40% the need for levodopa therapy in
cases of ParkinsonÕs Disease, a condition marked by severe dopamine deficiencies.
The increase in phenethylamine caused by selegiline may also contribute to its ther-apeutic
value for ParkinsonÕs, as it is known to promote the release of dopamine
and inhibit its transport. Although most valuable as an adjunct to levodopa therapy,
selegiline is somewhat effective as a monotherapy, improving scores on the Unified
ParkinsonÕs Disease Rating Scale by 5Ð30%.
The ÒFree Radical Theory of AgingÓ hypothesizes that the rate at which one
ages is proportional to the ratio of pro- to anti-oxidants. When the balance is tipped
towards pro-oxidants, ROS are more free to cause oxidative damage, hastening the
inhibit their activity. While MAO-A preferentially deaminates serotonin and nora-drenaline
and is selectively inhibited by clorgyline, MAO-B tends to catalyse the
reduction of dopamine and -phenethylamine and may be inhibited by aliphatic
propargylamines like selegiline [5].
RCH2NH2 + H2O + O2 -> RCHO + NH3 + H2O2 (1)
As a selective and irreversible inhibitor of MAO-B, selegiline prevents the
deamination of dopamine and -phenethylamine, thus increasing the concentra-tion
of those monoamines while restricting the production of hydrogen peroxide,
a pro-oxidant or Òreactive oxygen speciesÓ (ROS). By increasing dopamine lev-els,
selegiline forestalls and decreases by 30Ð40% the need for levodopa therapy in
cases of ParkinsonÕs Disease, a condition marked by severe dopamine deficiencies.
The increase in phenethylamine caused by selegiline may also contribute to its ther-apeutic
value for ParkinsonÕs, as it is known to promote the release of dopamine
and inhibit its transport. Although most valuable as an adjunct to levodopa therapy,
selegiline is somewhat effective as a monotherapy, improving scores on the Unified
ParkinsonÕs Disease Rating Scale by 5Ð30%.
The ÒFree Radical Theory of AgingÓ hypothesizes that the rate at which one
ages is proportional to the ratio of pro- to anti-oxidants. When the balance is tipped
towards pro-oxidants, ROS are more free to cause oxidative damage, hastening the
aging process. Selegiline is thought to tip the balance in the other direction in
part, at least, by inhibiting the metabolism of monoamines by MAO-B and thereby
diminishing the production of hydrogen peroxide. This action may seem even more
significant in light of reports that MAO-B levels begin increasing with age around
50Ð60, is more active in AlzheimerÕs and ParkinsonÕs patients, and is found in high
concentrations in AlzheimerÕs plaques [5].
Selegiline has, additionally, been demonstrated to protect against the oxidative
damage to serotonin terminals caused by large doses (40 mg/kg) of MDMA (12).
This could be explained by selegilineÕs inhibition of MAO-B: by interfering with
the deamination of the large amount of dopamine released by MDMA, it would
also inhibit the production of the ROS thought to cause the damage [21]. It seems
just as likely, however, that this damage could be prevented by the antioxidant
enzymes discussed below.
N
Figure 4: Pargyline
N
Figure 5: R-2HMP
The propargyl group also appear to protect against neurodegeneration by pre-venting
apoptosis, or programmed cell death. Marumaya et al have proposed that
selegiline and related compounds bond to a protein with a tertiary structure very
4
HN
Figure 6: Rasagiline, N-propargyl-1-(R)aminoindan
similar to that of MAO-B, triggering Òthe cellular process to repress the apoptotic
death program,Õ Õ [15].
Superoxide dismutase (SOD) and catalase are antioxidant enzymes (AOEs)
which work to prevent oxidative damage to the body and brain by reactive oxygen
species (ROS). Though Knoll initially found that selegiline increased the activity
of AOEs, his subsequent research with a different strain of rat failed to corroborate
this result. Further work by Kitani et al has done much to elucidate the relationship
of selegiline to AOEs, concluding that the dose-effect graph follows an inverse U
shape, increasing to a certain, optimal dose and declining steadily thereafter [9].
As an aside, the response of AOEs to selegiline is paralleled by that of the
lifespan of various animals (mice, rats, hamsters, and beagles) to the same. Both
dose-effect graphs follow an inverted U shape, and Kitani et al maintain this as the
primary support for their working hypothesis that the upregulation of AOEs and
extension of lifespan observed with selegiline treatment are causally connected.
This optimal dose is heaviliy dependent on the activity of the hepatic microso-mal
cytochrome P-450 enzyme responsible for the metabolism of selegiline, which
itself is dependent not only on the age, sex, and genetic strain of the organism, but
also on the length of time over which selegiline is administered. The difficulty of
extrapolating these results to humans is illustrated by studies in which Kitani ad-ministered
various doses of selegiline to our closer relatives, beagles and monkeys:
while a dose of 0.17 mg/kg, ÒroughlyÓ equivalent to that prescribed for ParkinsonÕs
Disease (10 mg/day), was most effective for young male monkeys, a much larger
dose of 1.0 mg/kg gave the best results for female beagles.
Other propargylamines share in selegilineÕs effect on AOEs, albeit with vary-ing
degrees of potency. Of those listed by Kitani et al, selegiline is the most ef-fective,
followed by rasagiline (6), R-2HMP (5), and R-2HP. Though the relation
of the larger structures of these molecules to their effects on SOD and catalase is
largely unknown, Kitani does expect that selegiline should be more potent than
desmethylselegiline, given that R-2HMP is more potent than its desmethyl deriva-tive
[9].
2 Catecholamine Activity Enhancement
Like many derivatives of phenethylamine, selegiline stimulates the activity of the
sympathetic system of the brain. As a catecholamine activity enhancer (CAE),
selegiline intensifies the response of catecholaminergic neurons by increasing the
impulse-mediated release of catecholamines. It is unique, however, in that it does
not displace catecholamines from their stores, which property tends to lead to de-pendence,
as exemplified by dextro-methamphetamine [12].
In a fascinating article entitled ÒSex, Performance, and Longevity,Ó Knoll es-tablishes
an apparently solid, heretofore unknown, link between sexual activity,
learning ability, and lifespan in rats via Òa hitherto unknown brain mechanism that
controls general activity and thereby, indirectly, the duration of life.Ó
Knoll first shows that the lifespan of normal, placebo treated rats is proportional
to their sexual activity and learning performance: rats predetermined to have ÒlowÓ
sexual and learning performance as measured by standard tests lived about 134
weeks, while those which scored as ÒhighÓ performers lived about 151 weeks, or
about 12% longer.
Finally, he reports that maintaining rats with a daily, 0.25 mg/kg dose of se-legiline
until death lengthened lifespan and increased scores in tests of sexual
and learning performance: selegiline-treated, low-performing rats lived about 152
weeks, or 13% longer than their untreated peers, and selegiline-treated, high-performing
rats lived about 185 weeks, or 22% longer.
At each step, increases in lifespan are linked with increases in sexual perfor-mance,
and each of these is tied to learning ability. Moreover, life-long mainte-nance
of rats on selegiline is shown to increase all three as compared to placebo-treated
peers; initially low-performing rats treated with selegiline outlive their un-7
treated, high-performing peers by roughly a month, improve in measures of sexual
and learning performance, and maintain their ability to perform beyond that of their
untreated peers [11].
3 Pharmacokinetics
Selegiline is administered therapeutically at a dose of 5-10 mg. It is taken up
by the body quickly, and reaches its peak concentration in the plasma within 30Ð
120 minutes. MAO-B is irreversibly inhibited by 90% within 30Ð90 minutes, and
remains so until it can be re-synthesized by the body Ð a period of up to 40 days.
Selegiline is primarily metabolized in the liver by the cytochrome P450 en-zyme
into desmethylselegiline (7), l-methamphetamine (9), and l-amphetamine
(8). These compounds are further metabolized by ring hydroxylation into p-hydroxy-amphetamine
(11), p-hydroxymethamphetamine, and p-hydroxy-N-propargylam-phetamine,
or by -carbon hydroxylation into ephedrine (10), norephedrine, pseudo-ephedrine,
and norpseudoephedrine.
Though selegiline is typically taken orally, transdermal administration may, in
some ways, be favorable. When first-pass metabolism in the liver is circumvented,
the maximum plasma concentration of selegiline is increased 60-fold, and the bal-ance
of metabolites is altered significantly, halving the production of (levo) am-phetamines
while increasing levels of desmethylselegiline, which is itself a propar-8
gylamine [5].
NH
Figure 7: Nordeprenyl, Desmethylselegiline
NH 2
Figure 8: Amphetamine
NH
Figure 9: Methamphetamine
OH
NH
Figure 10: Ephedrine
HO
NH 2
Figure 11: PHA, p-hydroxyamphetamine
Composed primarily of a phenethylamine base and a propargylamine group,
selegiline inherits characteristics of both. From phenethylamine, selegiline de-rives
its ability to enhance catecholamine activity, multiplying the response of cat-echolaminergic
nerves. From propargylamine, selegiline inherits its ability to in-hibit
monoamine oxidase B, prevent apoptosis, protect against oxidative damage
caused by the deamination of monoamines, and increase the activity of antioxidant
9
NH O
O
Figure 12: MDMA (Ecstasy), 3,4-methylenedioxymethamphetamine
OH
OH NH 2
Figure 13: Dopamine, 3,4-dihydroxyphenylethylamine
OH
OH
OH
NH
Figure 14: Epinephrine (Adrenaline)
OH
OH NH 2
OH
Figure 15: Norepinephrine
N O
O
Figure 16: MDPL, 3,4-methylenedioxy-N-propargylamphetamine [19]
10
COOH
Ph Ph Ph
COOMe
HN
Ph
COOCH 3
Ph
N N
CH 3 CH 2 OH
NH 2 NH 2
CH 3
CH 3 CH 3
4 NaBH
MeOH esterification HCOOH condensation
reduction
propargyl bromide LAH reduction
thionyl chloride
alkyl halide reduction
l¥phenylalanine
l¥deprenyl
Figure 17: Synthesis of l-deprenyl from phenylalanine [17]
enzymes. With the combination of these groups, selegiline exhibits more novel
properties, including CAE without catecholamine release, and offers a unique and
unlikely combination of mechanisms which work to make it a valuable treatment
for ParkinsonÕs Disease. Last, but not least, is evidence that it can actually extend
lifespan and preserve sexual and learning performance.
11

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