A review of the pharmacology of selegiline

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone.
Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons.
Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline.
Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.     

Release of monoamines from striatal slices by phenelzine and β-phenylethylamine

1. 1. Slices of striatum obtained from control rats were incubated with H-serotonin (³H-5HT) or ¹⁴C-dopamine (¹⁴C-DA) in the presence of pargyline; then, they were subjected to a rapid transfer technique during which they were washed either with a normal Krebs buffer or one containing known quantities of phenelzine (PEH) or β-phenylethylamine (PE).

2. 2. Both PEH and PE were able to stimulate releases of ³H-5HT and ¹⁴C-DA that were greater than control. More ¹⁴C-DA than ³H-5HT was released by both compounds. Much lower concentrations of PE than of PEH were required to stimulate monoamine release.

3. 3. Other rats were Injected intraperitoneally with behaviourally effective doses of either PEH or PE and were killed at various times.

4. 4. The concentrations of PEH or of PE in the striata of these animals were very high 15 min after I.P. Injection, but declined rapidly thereafter.

5. 5. These results may be Interpreted to suggest that after I.P. Injection, sufficient levels of PEH and PE were attained in the rat striatum to stimulate release of endogenous 5HT and DA.

A double blind comparative trial of nomifensin and desimipramine in depression

Summary The effect of nomifensin (Hoechst 36984), a synthetic psychotropic drug whose structure differs from MAO inhibitors and tricyclics, was studied in a double blind comparative trial with desimipramine in patients with various depressive syndromes. Forty-three patients (23 in the nomifensin group and 20 in the desimipramine group) were studied for 6 weeks. Clinical follow-up was done with the Wittenborn scale (WPRS), Hamilton's rating scale for depression (HRS), Zung's scale (SDS), and the PEN inventory. The average daily dose was nomifensin 84 mg and desimipramine 76 mg. Changes in HRS, WPRS and SDS showed statistically significant improvement with both treatments. A moderate anxiolytic effect was found in the nomifensin group, whereas medication had to be discontinued in two desimipramine-treated patients because of its drive-enhancing effect. Urinary phenylethylamine excretion rose in 2 out of 8 patients after 5 weeks of treatment with nomifensin.     

Membrane permeability of trace amines: Evidence for a regulated,activity‐dependent,nonexocytotic, synaptic release

Both pre‐ and post‐synaptic effects of trace amines have been demonstrated. The putative intracellular location of Trace Amine‐Associated Receptors necessitate that membrane transport processes be present in order for post‐synaptic effects to occur. Here we examine the ability of trace amines to cross synthetic (Fluorosomes) and native (synaptosomes) lipid bilayer membranes. Trace amines readily crossed Fluorosome membranes by simple diffusion, p‐tyramine (P = 0.01) and tryptamine (P = 0.0004) showing significantly faster diffusion than dopamine and 5‐HT, respectively, with diffusion half‐lives of 13.5 ± 4.1 (p‐tyramine) and 6.8 ± 0.7 seconds (tryptamine). Similarly, release of [³H]p‐tyramine and [³H]2‐phenylethylamine from pre‐loaded synaptosomes occurred significantly quicker than did [³H]dopamine (P = 0.0001), with half lives of 38.9 (p‐tyramine), 7.8 (2‐phenylethylamine) and 133.6 seconds (dopamine). This was, however, significantly slower than the diffusion mediated passage across Fluorosome membranes (P = 0.0001), suggesting a role for transporters in mediating trace amine release. Further, a pronounced shoulder region was observed in the synaptosome [³H]p‐tyramine release curve, suggesting that multiple processes regulate release. No such shoulder region was present for [³H]dopamine release. Surprisingly, both [³H]p‐tyramine (P = 0.001) and [³H]2‐phenylethylamine (P = 0.0001) release from synaptosomes was significantly decreased under depolarizing conditions. As expected, depolarization significantly increased [³H]dopamine release. The data presented indicate that the release of p‐tyramine and 2‐phenylethylamine from neuronal terminals occurs by a different mechanism than dopamine, and does not involve classical exocytosis. The data are consistent with an initial release of trace amines by simple diffusion, followed by an activity‐dependent regulation of synaptic levels via one or more transporter proteins. Synapse 67:656–667, 2013 . © 2013 Wiley Periodicals, Inc.     

The Genain quadruplets 25 years later: A diagnostic and biochemical followup

A biological and clinical followup of the Genain Quadruplets was initiated as a multilaboratory collaborative effort at the National Institute of Mental Health (NIMH). The quadruplets are 51-year-old monozygotic women previously studied with a battery of psychological and physiological tests 25 years ago at the NIMH. The present article (the first of a series of three) details the clinical history and course of the schizophrenic illness in each of the quadruplets and describes the biochemical measures determined. The findings of elevated urinary phenylethylamine excretion, decreased plasma dopamine-β-hydroxylase activity, and increased α-adrenergic receptor concentrations in all quadruplets warrant further genetic studies.     

Urinary excretion of O-methylated catecholamines,tyramine and phenyl-ethylamine by volunteers treated with tranylcypromine and CGP 11305 A

Summary To assess the effect of the new, selective, reversible MAO A inhibitor, CGP 11305 A (4-(5-methoxy-7-bromo-benzofuranyl-2-)piperidine HCl), on MAO A and B activity in man, the daily excretion of total normetanephrine (NMN), metanephrine (MN), 3-methoxytyramine (3-MT) and-phenylethylamine (PEA) was measured in the urine of healthy volunteers treated with weekly increasing doses from 40 to 150 mg/d. A similar study was carried out with tranylcypromine in weekly increasing doses from 10 to 25 mg/d. Both compounds increased the excretion of NMN; with CGP 11305 A, a plateau was obtained at 50 mg/d, and tranylcypromine 20 mg was more effective than 10 mg, and was also more active than the highest dose of CGP 11305 A. Increases in MN and 3-MT produced by the latter compound were comparable to that in NMN, whereas tranylcypromine had a biphasic effect on MN excretion, and caused only a small increase in 3-MT excretion. CGP 11305 A up to 150 mg/d did not alter total tyramine excretion, whereas tranylcypromine at 20 mg caused a definite increase. Tranylcypromine led to 4–6 fold increases in PEA output at 20 and 25 mg/d, but not at 10 mg. No such effect could be demonstrated for CGP 11305 A up to 150 mg/d. These results suggest that in man MAO A was inhibited by CGP 11305 A in daily dose of 40 mg or more, whereas it did not affect MAO B at up to 150 mg. Thus, it exhibited considerably greater selectivity than tranylcypromine, which showed only a slight preponderance of inhibition of the A-type enzyme.     

Lithium alters the stereoselectivity of monoamine oxidase in rat brain

Summary The effects of lithium on monoamine oxidase (MAO) in rat brain were studied in the presence of each enantiomer of tranylcypromine [(+)- and (–)-TCP]. The (+)-enantiomer was 25 times more potent than its antipode as MAO inhibitor. Lithium enhanced the inhibitory effect of (–)-TCP on MAO, but it did not affect actions of the (+)-enantiomer. Moreover, lithium influenced the stereo selective index for MAO, which suggests that lithium altered conformational features of the enzyme.     

1-(肉桂酰基)-4-(苯乙胺乙酰基)哌嗪马来酸盐对血小板聚集和血栓形成的影响

研究化合物1-(肉桂酰基)-4-(苯乙胺乙酰基)哌嗪马来酸盐的抗凝血和抗血小板作用。采用小鼠断尾法测定出血时间,玻片法测定凝血时间,采用大鼠动静脉旁路法考察对血栓形成的抑制作用,采用家兔血小板体内、体外聚集试验测定受试药对ADP诱导的体内、体外家兔血小板最大聚集率的影响。结果表明1-(肉桂酰基)-4-(苯乙胺乙酰基)哌嗪马来酸盐具有明显的抗凝血、抗血栓形成及抑制ADP诱导的血小板聚集的作用。