Age-related decline of various cognitive functions in well-experienced male rats treated with the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP).

Aging-associated cognitive disorders lack proper medication. To meet this need translation-wise, modification of the animal models is also required. In the present study, effect of the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP, a deprenyl derivative) on age-related cognitive decline was investigated in experienced, aged Long-Evans rats. During their lifetime, animals had acquired knowledge in various cognitive assays. Their performance in these tests was then parallel followed from the age of 27 months until their death meanwhile half of them were treated with BPAP. Cognitive performance in various tasks showed different sensitivities/resistances to age-related impairment. Pot jumping performance (motor skill-learning) started to impair first, at 21 months of age, followed by decreasing performance in five-choice serial reaction time task (attention) at 26 months. Navigation performance in Morris water maze (spatial learning) started to decline at 31 months. Performance in a cooperation task (social cognition) started to decline the latest, at 34 months. Our findings suggest that in this process, the primary factor was the level of motivation to be engaged with the task and not losing the acquired knowledge. The average lifespan of the tested rat population was 36 months. BPAP could not improve the cognitive performance; neither could it prolong lifespan. A possible reason might be that dietary restriction and lifelong cognitive engagement had beneficial effects on cognitive capabilities and lifespan creating a "ceiling effect" for further improvement. The results confirmed that experienced animals provide a translationally relevant model to study age-related cognitive decline and measure the effect of putative anti-aging compounds.

Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline.

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [3H]dopamine release without influencing the resting [3H]dopamine release from rat striatal slices in 10-10-10-9 mol/L concentrations. Rasagiline added in 10-13 to 10-5 mol/L concentrations did not alter the resting or electrically stimulated [3H]dopamine release. Rasagiline (10-9 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [3H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10-8-10-7 mol/L) also inhibited the stimulatory effect of selegiline on [3H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (-)methamphetamine (10-9 mol/L) also exhibited enhancer activity on [3H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1.

Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum.

The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly located metabotropic receptor. Trace and classic amines, amphetamines, act as agonists on TAAR1; they activate downstream signal transduction influencing neurotransmitter release via intracellular phosphorylation. Our aim was to check the effect of the catecholaminergic activity enhancer compound ((-)BPAP, (R)-(-)-1-(benzofuran-2-yl)-2-propylaminopentane) on neurotransmitter release via the TAAR1 signaling. Rat striatal slices were prepared and the resting and electrical stimulation-evoked [3H]dopamine release was measured. The releaser (±)methamphetamine evoked non-vesicular [3H]dopamine release in a TAAR1-dependent manner, whereas (-)BPAP potentiated [3H]dopamine release with vesicular origin via TAAR1 mediation. (-)BPAP did not induce non-vesicular [3H]dopamine release. N-Ethylmaleimide, which inhibits SNARE core complex disassembly, potentiated the stimulatory effect of (-)BPAP on vesicular [3H]dopamine release. Subsequent analyses indicated that the dopamine-release stimulatory effect of (-)BPAP was due to an increase in PKC-mediated phosphorylation. We have hypothesized that there are two binding sites present on TAAR1, one for the releaser and one for the enhancer compounds, and they activate different PKC-mediated phosphorylation leading to the evoking of non-vesicular and vesicular dopamine release. (-)BPAP also increased VMAT2 operation enforcing vesicular [3H]dopamine accumulation and release. Vesicular dopamine release promoted by TAAR1 evokes activation of D2 dopamine autoreceptor-mediated presynaptic feedback inhibition. In conclusion, TAAR1 possesses a triggering role in both non-vesicular and vesicular dopamine release, and the mechanism of action of (-)BPAP is linked to the activation of TAAR1 and the signal transduction attached.

Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice.

Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects. We monitored by repeated Auditory Brainstem Response (ABR) measurements the effect of chronic per os selegiline administration on the hearing function in BALB/c and DBA/2J mice, which strains exhibit moderate and rapid progressive high frequency hearing loss, respectively. The treatments were started at 1 month of age and lasted until almost a year and 5 months of age, respectively. In BALB/c mice, 4 mg/kg selegiline significantly mitigated the progression of ARHL at higher frequencies. Used in a wide dose range (0.15-45 mg/kg), selegiline had no effect in DBA/2J mice. Our results suggest that selegiline can partially preserve the hearing in certain forms of ARHL by alleviating its development. It might also be otoprotective in other mammals or humans.

Inhibitory Effect of (2R)-1-(1-Benzofuran-2-yl)-N-propylpentan-2-amine on Lung Adenocarcinoma.

BPAP is a potent enhancer substance with catecholaminergic and serotoninergic activity in the brain. It was discovered that it is also effective against certain types of experimental cancers, showing the most promising results in case of lung cancer. That is why we tested its efficacy in two different doses in a newly developed EGFR wild type mouse lung adenocarcinoma xenograft model. Experiments were conducted on FVB/N and SCID mouse strains treated with low and high dose of BPAP. Body weight, survival, and tumor volumes were recorded. Furthermore, the activity of major signaling pathways of NSCLC such as MAPK and Akt/mTOR as well as cell cycle regulation were determined. Significant inhibition of tumor growth was exerted by both doses, but the mechanism of action was different. High dose directly inhibited, whereas low dose activated the main signaling pathways. Exposure to low dose BPAP resulted in elevated activity of the mTOR pathway together with p16INK-induced cell cycle arrest, a typical feature of geroconversion, a senescent state characterized by loss of cell proliferation. Finally the events culminated in cell cycle inhibition point in case of both doses mirrored by the decrease of cyclin D1, CDK4 and PCNA. In addition, BPAP treatment had a beneficial effect on bodyweight suggesting that the compound at least in part is able to compensate the cancer-related wasting. In view of the low toxicity and confirmed antitumor effect of BPAP against experimental lung adenocarcinoma, this novel compound deserves further attention.

Synthetic enhancer compounds, besides acting on biogenic amine system, influence the glutamate transmission and stress response.

Pharmaceutically available enhancer selegiline/(-)-deprenyl (DEP) in the clinically used dose shows antidepressant effect, but nothing is known about this effect in enhancer dose, and its effect on co-morbid anxiety. Moreover, data about the antidepressant/antianxiety effects of the serotonin-influencing enhancer, (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) are also missing. The aim of the present paper is to establish the role of enhancer regulation in anxiety and follow the changes in the phosphorylation of glutamate subunits in prefrontal cortex as well as stress-related organ and hormonal changes as possible background mechanism. The effect of 3-week-treatment of rats with specific (0.001 mg/kg for DEP, 0.0001 mg/kg for BPAP) and non-specific (0.1 mg/kg for DEP, 0.05 mg/kg for BPAP) enhancer doses were evaluated on anxiety-like behavior in the elevated plus maze (EPM) and open-field (OF) tests. Phosphorylated glutamatergic GluR1 and GluN2B subunits were analyzed by Western blot. Changes in the stress-regulatory system were evaluated by measuring the organ weights and blood corticosterone concentrations. Non-specific enhancer doses had a tendency for anxiolysis on EPM, while only 0.1 mg/kg DEP elevated motility in OF. Specific enhancer doses significantly increased the expression of both glutamatergic receptor subunits; non-specific doses elevated only pGluR1. Treatments had no effects on stress-like organ weights; however, the specific enhancer doses significantly reduced the dark phase resting corticosterone levels. The study proved the enhancer-sensitivity of the glutamatergic transmitter system and suggested enhancer-induced stabilization of stress-hormone levels without major impact on non-stimulated anxiety-like behavior.

Geroprotection in the future. In memoriam of Joseph Knoll: The selegiline story continues.

In memoriam of Joseph Knoll: the selegiline story continues.

[The role of parkin in Parkinson's disease]. / A parkin szerepe a Parkinson-kórban.

Parkin (Parkinson juvenile disease protein 2) is a ~52 kDa (426 amino acid) enzyme protein, encoded by PARK2 gene and located on the 6q chromosome. It plays an important role in the ubiquitin-proteasome system and acts as a regulator of protein breakdown. Parkin is located in the cytoplasma until a sustained depolarization occurs as a result of which it is translocated to the mitochondrial surface and induces the degradation of various membrane proteins which are candidates for mitophagia. Parkin is essential for cellular mitochondrial integrity. Parkin mutation leads to the accumulation of missfolded, aggregated proteins and degenerated mitochondria. The role of these changes in the pathomechanism of neurodegenerative diseases is well-known. It was a general belief for a long time that Parkinson's disease is without genetic component a sporadic disease. In 1997 a point mutation was, however, discovered in the α-synuclein gene, which caused dominantly inherited parkinsonism. At least 10 other genes were thereafter detected the mutation or deletion of which cause monogenic parkinsonism. Parkin mutation is responsible for about 50% of familial cases and for 10 to 20% of youth cases. According to the present views the improper regulation of protein aggregation and a dysfunction of the ubiquitin-proteasome system may be the common pathway of sporadic and hereditary Parkinson's disease. In the future it might have therapeutic value that parkin has versatile neuroprotective activity (against α-synuclein toxicity, proteasomal dysfunction, oxidative stress, kainite-induced and dopamine-mediated toxicity) as a result of which any reduction of parkin level or activity may cause damage in neuronal integrity.

[The role of alpha-synuclein in Parkinson's disease]. / Az α-szinuklein szerepe Parkinson-kórban.

α-synuclein, a small protein (140 amino acids) encoded by the SNCA gene is the best known isoform of the synuclein protein family. Though its physiological role is still not fully clarified, there is growing experimental evidence for a causal role of α-synuclein in the so-called conformational-neurodegenerative diseases. Conformational changes in the structure of the native soluble protein form insoluble neurotoxic aggregates and finally contribute to the formation of inclusion Lewy-bodies and Lewy-neurites. Neurodegeneration first hits the olfactory system, the peripheral autonomic nervous system, the enteric nervous system and the dorsal vagal motoneurons. The middle stage of the disease hits the dopaminergic neurons of the substantia nigra; and the neocortex is affected only in the late stage of the disease. This precise order of neurodegeneration is not always valid, but increases the likelihood that Lewy-bodies and neurodegenaration spread to intact areas in a prion-like way. Prions are infectious proteins which do not contain nucleic acids and cause diseases because they form toxic aggregates and filaments by misfolding in a ß-sheet-rich conformation. The misfolded protein behaves like a template inducing conformational change in the wild type proteins causing cross-reaction and leading to neurodegeneration. Later, the defective proteins may infect healthy nerve cells, thus neurodegeneration is extended. Growing experimental evidence shows that monomers and aggregates of α-synuclein are secreted via exocytosis from damaged nerve cells and taken up via endocytosis by healthy nerve cells furnishing evidence for the prion-like role of α-synuclein.

Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline.

BACKGROUND: (-)-Deprenyl and rasagiline are classified as selective inhibitors of B-type MAO. The DATATOP study revealed that the administration of (-)-deprenyl to untreated patients with Parkinson's disease (PD) significantly delays the need for levodopa therapy (Parkinson Study Group, 1989). Rasagiline was ineffective in this respect (Parkinson Study Group, 2002). The aim of this paper is to explain the reasoning behind the differentiation between (-)-deprenyl and rasagiline. METHODS: In the shuttle box the acquisition of a two way conditioned avoidance response (CAR) was analyzed on male Wistar rats during 5 consecutive days. Tetrabenazine-treatment (1mg/kg sc) depletes the transmitters from their stores in the nerve terminals of the catecholaminergic neurons and blocks the acquisition of a CAR. Catecholaminergic activity enhancer (CAE) substances [(-)-deprenyl, (-)-BPAP] fully antagonize the tetrabenazine-induced learning deficit. Using (-)-deprenyl and (-)-BPAP as reference substances, we measured the effect of rasagiline and J-508 in this test. Rasagiline is the desmethyl-analog of J-508, described by Knoll in 1978. RESULTS: In contrast to (-)-deprenyl and (-)-BPAP, J-508 and rasagiline were found in the shuttle box test to be devoid of the CAE effect. CONCLUSIONS: Since convincing experimental and clinical evidence speaks in favor for the conclusion that the catecholaminergic activity enhancer (CAE) effect of (-)-deprenyl is responsible for the significantly delayed need for levodopa therapy in untreated patients with PD (Knoll, 2012) and rasagiline is devoid of the CAE effect, this might explain why "...based on current evidence, rasagiline cannot be said to definitely have a disease-modifying effect" [Robottom, 2011].

[Guidelines on the pharmacotherapy of the dental patient during pregnancy]. / A várandós nok gyógyszeres kezelésének irányelvei a fogorvosi gyakorlatban.

Physiological differences occuring in pregnancy modify certain steps of dental treatments. Since in our everyday practice we meet expectant patients, we have to be aware of what kind of changes does this transitional state require from the dentist, how to do a good timing in the course of dental treatment, which are those medicaments that can be used safely and those which should be avoided. The summerized data in the article are to contribute the safe choice of the possibly necessary antibiotics during the treatments. Besides, dental care should not be delayed due to our doubts about local anestetics, because it may carry serious consequences later. Relying on the most up-to-date facts, moreover, we mention the guidelines of the use of analgesics during pregnancy in dentistry. The treatment of pregnant women does not differ to a high degree from those who are non-pregnant, yet some of its viewpoints need special attention and we have to take them into consideration in order to do the appropriate medical work. Basically, in our opinion, before every dental and dental surgical intervention it is essential to consult with the patient's gynaecologist and in agreement with him/her to determine the course of the medicinal treatment.

[The feasibility of synthetic enhancer substances for preventive nanotherapy]. / Preventív nanoterápiás lehetöségek szintetikus enhancer anyagokkal.

Nanotechnology, the great promise of the 21st century, may revolutionize also the art of healing. Previously unexpected broadening of diagnostic procedures and methods to deliver specific drugs acting in lower than nanomolecular concentrations right to the target cells may play a crucial role in the rapid development of preventive medicine. In this context, (-)-deprenyl/selegiline, a drug developed 40 years ago and still world-wide used to treat Parkinson's disease, Alzheimer's disease and depression, by enhancing the activity of catecholaminergic neurons in the brain stem via a previously unknown mechanism [catecholaminergic activity enhancer (CAE) effect], is a highly promising experimental tool for further research in this direction. The same fits for (-)-BPAP, the newly developed enhancer substance, 100 times more potent than (-)-deprenyl, which in contrast to the latter is not only an enhancer of the catecholaminergic neurons but also of the serotonergic neurons in the brain stem. Tiny amounts of enhancer substances are closed in liposomes and marked with a specific signal to help identify the exact location of the target cells, through the activation of which the drug exerts its specific enhancer effect. The method also offers an approach to better understand the up-to-the-present unknown mechanism of the enhancer effect.

[Slowing the age-induced decline of brain function with prophylactic use of (-)-deprenyl (Selegiline, Jumex). Current international view and conclusions 25 years after the Knoll's proposal]. / Az agymüködés korfüggö hanyatlásának lassítása (-)-deprenil (Selegilin, Jumex) profilaktikus adagolásával. A 25 éves Knoll javaslat mai nemzetközi megítélése és tanulságai.

Due primarily to developments in immunology, chemotherapy and hygiene the estimated life expectancy at birth increased during the last century from about 55 years to 80 years. Since the human Technical Life Span (TLSh) is about 120 years and life expectancy is today steadily increasing by about 2.2 months/year, a life span of 100 years may appear quite soon. Knoll developed (-)-deprenyl, the first anti-aging drug, the prophylactic administration of which increased significantly the average life span of animals. (-)-Deprenyl became a world-wide used experimental tool as the first selective inhibitor of B-type MAO and being the unique MAO inhibitor free of the cheese effect was introduced to treat Parkinson's disease, because it could be administered in combination with levodopa without side effects. However, Knoll demonstrated in his later work that (-)-deprenyl has enhancing qualities already in femto-picomolar concentrations, which leave MAO-B activity unchanged, and the activity of the catecholaminergic neurons in the brain stem and this previously unknown 'enhancer effect' is responsible for the peculiar therapeutic benefits caused by (-)-deprenyl. Knoll proposed 25 years ago to slow the aging of the brain, the decay of behavioral performance, prolong life, and prevent or delay the onset of age-related neurodegenerative diseases such as Parkinson's and Alzheimer's via the prophylactic daily administration of 1 mg (-)-deprenyl. At present (-)-deprenyl belongs to the best known anti-aging drugs and a rapidly growing number of people are already trying to slow the aging of their brain by taking (-)-deprenyl as a prophylactic agent. Nevertheless, up to the present, an exact analysis with placebo control of the capacity of (-)-deprenyl to prevent or delay the onset of neurodegenerative diseases is still missing. It is already very much on the map to perform such a study with this world-wide highly esteemed Hungarian drug.

[A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508]. / A (-)-deprenil, az N-metilprogargilamin-1-aminoindan (J-508) és a J-508 dezmetil analógjának (rasagilin) összehasonlító farmakológiai analízise.

N-methylpropargylamine-1-aminoindane (J-508), a strong releaser of catecholamines was described 30 years ago as a more potent selective inhibitor of MAO-B than (-)-deprenyl (Knoll 1978). In 2007 the desmethyl-analogue of J-508 (rasagiline) was registered as a new selective inhibitor of MAO-B and a possible substitute for (-)-deprenyl in therapy. The discovery of the enhancer regulation, the realization that catecholaminergic and serotonergic neurons in the brain stem are enhancer-sensitive neurons, phenylethylamine (PEA) and triptamine are endogenous enhancer substances, (-)-deprenyl is a PEA-derived synthetic enhancer substance, and finally the development of (-)-BPAP, a tryptamine-derived, 100 times more potent synthetic enhancer substance than (-)-deprenyl, made it clear that the enhancer effect of (-)-deprenyl is primarily responsible for the therapeutic benefits of this drug. To compare the pharmacological spectrum of (-)-deprenyl and rasagiline was the aim of this study. The ability of rats to acquire a two way conditioned avoidance response (CAR) in the shuttle box was analyzed during 5 consecutive days. Tetrabenazine treatment (1 mg/kg, s.c.) depletes from their stores the transmitters of the catecholaminergic neurons of the brain stem. Since the activation of the cortical neurons via the noradrenergic neurons in the brain stem is sine qua non for the acquisition for a CAR, rats treated with tetrabenazine are unable to learn in the shuttle box. To block the activity of MAO-A (clorgyline) or to treat rats with an enhancer substance [(-)-BPAP] are the two possibilities to antagonize the learning deficit caused by tetrabenazine. We compared in shuttle box experiments the effect of (-)-deprenyl, (-)-desmethyl-deprenyl, J-508 and desmethyl-J-508 (rasagiline) on the learning ability of rats pretreated with tetrabenazine. We used as a reference substance clorgyline to demonstrate the effect of a selective MAO-A inhibitor, and (-)-BPAP to demonstrate the effect of a selective enhancer substance. (-)-Deprenyl and (-)-desmethyl-deprenyl acted, like (-)-BPAP, in low doses as enhancer substances and in very high doses as MAO-A inhibitors. J-508 and rasagiline proved to be devoid of the enhancer property and in doses which are known to block MAO-A, they antagonized the effect of tetrabenazine, like clorgyline. Thus, rasagiline can not be a substitute for (-)-deprenyl in therapy.

Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane.

Because of the high number of therapy-resistant depressions and the growing number of suicides, there is still a great need for the development of antidepressants with a new pharmacological spectrum. The finding that phenylethylamine and tryptamine are endogenous enhancers of the impulse propagation mediated release of catecholamines and serotonin in the brain, and the development of synthetic enhancer substances opened the possibility to stimulate catecholaminergic and serotonergic neurons in the brain stem via a previously unknown mechanism. (-)-Deprenyl, a prototype of the phenylethylamine-derived synthetic enhancer substances, stimulates the catecholaminergic neurons in the brain but is almost ineffective on the serotonergic neurons. R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, (-)-BPAP, the recently developed tryptamine-derived selective synthetic enhancer substance, is a hundred times more potent enhancer of the catecholaminergic neuronal activity than (-)-deprenyl, and is also a highly potent stimulant of the serotonergic neurons. Evaluation of the peculiar pharmacological profile, the high potency and unusual safeness and tolerability of (-)-BPAP cherish the hope that this compound by itself and in combination with uptake inhibitors may improve the effectiveness of drug therapy in major depression and diminish the number of therapy resistant cases.

Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives.

The discovery of enhancer regulation in the mesencephalon and the concept that it plays a key role in the operation of innate and acquired drives [Neurochem. Res. 28 (2003) 1187] sets the trace amines (TAs) in their true physiological perspective. The regulation is defined as the existence of enhancer-sensitive neurons in the brain capable of working in a split-second on a high activity level due to endogenous enhancer substances. For the time being, only beta-phenylethylamine (PEA) and tryptamine are the experimentally analyzed examples. (-)-Deprenyl (selegiline), widely used in Parkinson's disease and Alzheimer's disease today, and known as the first selective monoamine oxidase (MAO) type-B inhibitor for decades, was identified as a PEA-derived synthetic mesencephalic enhancer substance. An important and convincing confirmation of the enhancer concept was the recent development of a highly specific and potent tryptamine-derived synthetic mesencephalic enhancer substance, (-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP]. This substance, which is specific and hundreds of times more potent than selegiline, is now the best experimental tool to study the enhancer regulation in the mesencephalon and a promising candidate to significantly surpass the therapeutic efficiency of selegiline in depression, Parkinson's disease, and Alzheimer's disease.

The use of the synthetic enhancer substances (-)-deprenyl and (-)-BPAP in major depression.

There is still a great need for the development of antidepressants with a new pharmacological spectrum. The finding that phenylethylamine and tryptamine are endogenous enhancers of the impulse propagation mediated release of catecholamines and serotonin in the brain, and the development of synthetic mesencephalic enhancer substances opened the possibility to stimulate catecholaminergic and serotonergic neurons in the mesencephalon via a previously unknown mechanism. (-)-Deprenyl, a prototype of the phenylethylamine-derived synthetic enhancer substances, stimulates the catecholaminergic neurons in the brain but is almost ineffective on the serotonergic neurons. R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, (-)-BPAP, the recently developed tryptamine-derived selective synthetic mesencephalic enhancer substance, a hundred times more potent compound than (-)-deprenyl, acts also on the serotonergic neurons. The evaluation of the special pharmacological profile of the synthetic mesencephalic enhancer substance, especially the high potency and the unusual safety and tolerability of (-)-BPAP provide hope that this compound may in the future significantly improve the effectiveness of drug therapy in major depression and its combination with uptake inhibitors may substantially diminish the number of therapy resistant cases.

Stimulation of the catecholaminergic and serotoninergic neurons in the rat brain by R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, (-)-BPAP.

R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane HCl, (-)-BPAP, the recently developed selective and much more potent catecholaminergic/serotoninergic enhancer (CAE/SAE) substance than (-)-deprenyl enhances the performance of midbrain neurons, both in vivo and ex vivo, in a characteristic complex manner, presenting one bell shape dose/concentration effect curve in the low nanomolar range and another at higher micromolar range. For example, 4.7 +/- 0.10 nmol/g wet weight noradrenaline was released within 20 min from the quickly removed locus coeruleus of saline treated rats. This amount was increased 30 min after the subcutaneous administration of 0.0005 mg/kg (-)-BPAP to 15.4 +/- 0.55 nmol/g (P < 0.001). However, following the injection of a hundred times higher, 0.05 mg/kg, dose of (-)-BPAP, the amount of noradrenaline (4.3 +/- 0.25 nmol/g) released from the locus coeruleus did not differ from the control value. In ex vivo experiments, when the isolated locus coeruleus was soaked in an organ bath containing (-)-BPAP, the release of noradrenaline was significantly enhanced from 10(-16) M concentration, reached a peak effect at 10(-13) M concentration, but 10(-10) M (-)-BPAP was ineffective. A significant enhancer effect was detected also in the high concentration range from 10(-8) M, the peak effect was reached at 10(-6) M concentration and 10(-5) M (-)-BPAP was ineffective. (-)-BPAP enhanced in the low concentration range the performance of dopaminergic and serotoninergic neurons with a peak effect at 10(-13) and 10(-12) M concentration, respectively. The results with (-)-BPAP, the highly specific artificial enhancer substance, suggest that (i) high and low affinity "enhancer" receptors may exist in the brain, and (ii) that they may be identified with the recently cloned family of the "trace amine" receptors, activated by beta-phenylethylamine and tryptamine, the prototypes of the endogenous enhancer substances.