Deprenyl the PEADerived Enhancer Substance

The Parkinson's-Reversing Breakthrough

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(-)-Deprenyl (Selegiline), developed in the early 1960s as a new spectrum psychostimulant and potent MAO inhibitor, later proved to be, as the first selective inhibitor of MAO-B, indispensable for investigating the nature and function of B-type MAO. Hundreds of clinical studies with the drug were designed thereafter in the firm belief that selective blockade of MAO-B was responsible

Fig.3.3. Significant enhancement of norepinephrine release from the locus coeruleus of rats isolated 30 min after the subcutaneous administration of a single dose of (-)-deprenyl. The amount of norepinephrine released from the tissue within 20 min following the administration of different doses of (-)-deprenyl was measured according to Knoll and Miklya (1995). Horizontal lines to the right of the graph bars show the SEM. Paired Student's f-test.

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LOCUS COERULEUS

RELEASE OF NOREPINEPHRINE

for all the effects that followed (-)-deprenyl medication. Realizing, however, that PEA is an endogenous mesencephalic enhancer substance and a releaser of catecholamines, while (-)-deprenyl is a PEA-derived synthetic mesencephalic enhancer substance devoid of any catecholamine-releasing property, it became clear that the enhancer effect of (-)-deprenyl was responsible for the majority of the beneficial effects of the drug described in various experimental and clinical studies (see Knoll 1998,2001, for review).

SUBSTANTIA NIGRA

TUBERCULUM OLFACTORIUM

IH IH

STRIATUM

RELEASE OF DOPAMINE (nmol/g wet weight)

Fig.3.4. Significant enhancement of dopamine release from the substantia nigra, tuberculum olfactorium, and striatum of rats, respectively, isolated 30 min after the subcutaneous administration of a single dose of (-)-deprenyl. The amount of dopamine released from the tissue within 20 min following the administration of different doses of (-)-deprenyl was measured according to Knoll and Miklya (1995). Horizontal lines to the right of the graph bars show the SEM. Paired Student's f-test. *P < 0.05, **P < 0.02, ***P < 0.01

PEA, rapidly metabolized by MAO, is short acting and its enhancer effect can be detected in in vitro experiments only (see Fig. 3.1). Since (-)-deprenyl is not rapidly metabolized, its effect can be measured quantitatively in vivo. The subcutaneous administration of (-)-deprenyl enhanced the activity of the catecholaminergic neurons in a dose-dependent manner. This effect is shown on noradrenergic neurons (Fig. 3.3) and on dopaminergic neurons (Fig. 3.4). (-)-Deprenyl treatment, however, did not enhance the activity of serotonergic neurons (Fig. 3.5). (-)-Deprenyl is a PEA-derived enhancer substance and its in vivo ineffectiveness on serotonergic neurons is in accord with the finding that PEA was much less potent than tryptamine in enhancing the activity of the serotonergic neurons in the in vitro experiments, too (cf. Fig. 3.1 with Fig. 3.2).

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RAPHE

RELEASE OF SEROTONIN (nmol/g wet weight)

Fig.3.5. Lack of enhancement of serotonin release from the raphe of rats isolated 30 min after the subcutaneous administration of a single dose of (-)-deprenyl. The amount of serotonin released from the tissue within 20 min following the administration of different doses of (-)-deprenyl was measured according to Knoll and Miklya (1995). Horizontal lines to the right of the graph bars show the SEM. Paired Student's i-test was used for statistical analysis. None of the applied doses of (-)-deprenyl enhanced the release of serotonin significantly, the highest dose even decreased the release significantly. *P < 0.05

Since (-)-deprenyl is a highly potent and selective inhibitor of MAO-B, we performed a structure-activity relationship study to develop a deprenyl-derived enhancer substance that is free of the MAO-B inhibitory property (Knoll et al. 1992a). (-)-1-Phenyl-2-propylaminopentane [(-)-PPAP] has been chosen as our reference substance with this pharmacological profile.

Figure 3.6 shows the chemical structure and pharmacological spectrum of PEA and its four most representative synthetic derivatives.

ß-PHENYLETHYLAMINE (PEA)

ENHANCER RELEASING RELATION EFFECT EFFECT TO MAO

SUBSTRATE TO MAO-B

AMPHETAMINE

CH3 H H

WEAK MAO INHIBITOR

METHAMPHETAMINE

CH3 CH3 H

WEAK MAO INHIBITOR

(-)-1-PHENYL-2-METHYL-N-METHYL-PROPARGYL-AMINE, (-)-DEPRENYL

CH3 CH3 C3H3 +

POTENT MAO-B INHIBITOR

Fig.3.6. The chemical structure and pharmacological spectrum of PEA and its most representative synthetic derivatives. Taken from Knoll 2001

Fig.3.7. Significant enhancement of nore-pinephrine release from the locus coeruleus of rats isolated 30 min after the subcutaneous administration of a single dose of (-)-BPAP. The amount of norepinephrine released from the tissue within 20 min following the administration of different doses of (-)-BPAP was measured according to Knoll and Miklya (1995). Horizontal lines to the right of the graph bars show SEM. Paired Student's i-test. *P < 0.05, **P < 0.01, ***P < 0.001

LOCUS COERULEUS

RELEASE OF NOREPINEPHRINE (nmol/g wet weight)

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