title: Transporter-mediated actions of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane.
abstract: R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP] is a catecholaminergic and serotonergic activity enhancer that increases impulse-evoked catecholamine and serotonin release from nerve terminals, and is a candidate for symptomatic treatment of early Parkinson's disease. We now report the catecholamine and serotonin transporter-mediated actions of (-)-BPAP. The effects of (-)-BPAP on inhibition of neurotransmitter uptake and radioligand binding were assessed using human embryonic kidney 293 cells (HEK 293 cells) expressing cDNA for the human dopamine transporter (hDAT), norepinephrine transporter (hNET), and serotonin transporter (hSERT). The IC(50) values for the effects of (-)-BPAP on [3H]dopamine, [3H]norepinephrine, and [3H]serotonin uptake were 42+/-9, 52+/-19, and 640+/-120 nM, respectively. The IC(50) values for the effects of (-)-BPAP on [125I]3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid methyl ester ([125I]RTI-55) binding to hDAT, hNET, and hSERT were 16+/-2, 211+/-61, and 638+/-63 nM, respectively. The effects of (-)-BPAP on spontaneous and tyramine-induced norepinephrine and dopamine release from rat brain synaptosomes using a superfusion system were also assessed. Tyramine but not (-)-BPAP potentiated norepinephrine release. Furthermore, (-)-BPAP inhibited tyramine-induced norepinephrine release. Thus, (-)-BPAP may block tyramine-induced adverse effects such as hypertensive crisis. The actions of (-)-BPAP on the spontaneous and tyramine-induced dopamine release resembled its effects on norepinephrine release. We conclude that (-)-BPAP is not only catecholaminergic and serotonergic activity enhancer, but also a norepinephrine and dopamine uptake inhibitor and a weak serotonin uptake inhibitor that does not possess a tyramine-like action on catecholamine release, and is an inhibitor of tyramine-induced release of norepinephrine.
authors.affiliation: Institute of Research and Development, Fujimoto Pharmaceutical Corporation, 1-3-40 Nishiotsuka, Matsubara, Osaka 580-0011, Japan. soyaku@fujimoto-pharm.co.jp
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Shimazu
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsunekawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Yoneda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C404200:1-(benzofuran-2-yl)-2-propylaminopentane; D001572:Benzofurans; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine