ABSTRACT
The catecholaminergic and serotoninergic neurons in the brain change their performance according to the physiological need via a catecholaminergic/serotoninergic activity enhancer (CAE/SAE) mechanism. Phenylethylamine (PEA), tyramine and tryptamine are the presently known endogenous CAE/SAE substances which enhance the impulse propagation mediated release of catecholamines and serotonin in the brain. A PEA derivative, (-)deprenyl (selegiline), known as a selective inhibitor of MAO-B, is for the time being the only CAE/SAE substance in clinical use. Aiming to develop a selective CAE/SAE substance much more potent than (-)deprenyl, a series of new 1-aryl-2-alkylaminoalkanes, structurally unrelated to PEA and the amphetamines, was designed and prepared. Among them, (-)1-(benzofuran-2-yl)-2-propylaminopentane ((-)BPAP) was selected as a promising candidate substance for further studies. (-)BPAP significantly enhanced in rats the impulse propagation mediated release of catecholamines and serotonin in the brain 30min after acute injection of 0.36nmol/kg sc. In the shuttle box, (-)BPAP was in rats about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance. (+/-)BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14)-10(-15)M concentration.
Subject(s)
Benzofurans/pharmacology , Brain/drug effects , Catecholamines/metabolism , Neurons/drug effects , Serotonin/metabolism , Amphetamines/chemical synthesis , Amphetamines/pharmacology , Amyloid/analysis , Amyloid/antagonists & inhibitors , Animals , Avoidance Learning/drug effects , Benzofurans/chemical synthesis , Benzofurans/metabolism , Brain/physiology , Brain Stem/metabolism , Cells, Cultured , Electric Stimulation , Hippocampus/cytology , Monoamine Oxidase/drug effects , Phenethylamines/chemistry , Phenethylamines/pharmacology , Rats , Selegiline/chemistry , Selegiline/pharmacology , Structure-Activity Relationship , Tryptamines/pharmacology , Tyramine/pharmacologyABSTRACT
Volatile by-products in the chlorination of 3 humic acids as naturally-occurring substances and 37 nitrogen compounds normally found in excrement were analyzed, and as result kynurenine, a urinary metabolite of tryptophan was found a suitable model compound for dichloroacetonitrile-forming precursors. Possible pathways for the formation of chlorination by-products from kynurenine were also proposed by identification and kinetic properties of by-products decomposed further from each product.
