(-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain

Abstract

1. The brain constituents beta-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain ('catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (-)Deprenyl (Selegiline) and (-)1-phenyl-2-propylaminopentane [(-)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property. 2. By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)BPAP] was selected as a potential follower of (-)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain. 3. (-)BPAP significantly enhanced in 0.18 micromol 1(-1) concentration the impulse propagation mediated release of [(3)H]-noradrenaline and [(3)H]-dopamine and in 36 nmol 1(-1) concentration the release of [(3)H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10(-12) - 10(-14) M (-)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14) M concentration. In rats (-)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 microg kg(-1) s.c. In the shuttle box, (-)BPAP in rats was about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance.

Figure 1

The chemical structure and pharmacological spectrum of PEA and tryptamine derived CAE substances.

Figure 2

Release of [³H]-noradrenaline from isolated rat brain stem before and after electrical stimulation, in the absence and presence of PEA, tryptamine and (−)BPAP, respectively. (N=8). Each column represents the amount of [³H]-noradrenaline in picomoles released in a 3 min collection period. Vertical lines show s.e.m. Paired Student's t-test. ^*P<0.05, ^**P<0.02, ^***P<0.01, ^****P<0.001.

Figure 3

Release of [³H]-dopamine from isolated rat brain stem before and after electrical stimulation, in the absence and presence of PEA, tryptamine and (−)BPAP, respectively (N=8). Each column represents the amount of [³H]-dopamine in picomoles released in a 3 min collection period. Vertical lines show s.e.m. Paired Student's t-test. ^*P<0.05, ^**P<0.02, ^***P<0.01, ^****P<0.001.

Figure 4

Release of [³H]-serotonin from isolated rat brain stem before and after electrical stimulation, in the absence and presence of PEA, tryptamine and (−)BPAP, respectively. (N=8). Each column represents the amount of [³H-]-serotonin in picomoles released in a 3 min collection period. Vertical lines show s.e.m. Paired Student's t-test. ^*P<0.05, ^**P<0.02, ^***P<0.01, ^****P<0.001.

Figure 5

Survival of cultured rat hippocampal neurons in the absence (Control=100%) and presence of 20 μM β-amyloid (22.41±7.20%) and the protective effect of BPAP on β-amyloid induced neurotoxicity. Vertical lines show s.d. Statistics: Dunnett's t-test.