title: BF-1--a novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs.
abstract: Serotonin 5-HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, dopamine D1 and D2 as well as muscarinic M1 and M2 receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-α-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects.
authors: Biofrontera Bioscience GmbH, Hemmelrather Weg 201, 51377 Leverkusen, Germany.
authors: Beate
authors: B
authors: Schmitz
authors: Biofrontera Bioscience GmbH, Hemmelrather Weg 201, 51377 Leverkusen, Germany.
authors: Christoph
authors: C
authors: Ullmer
authors: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors: Daniel
authors: D
authors: Segelcke
authors: Biofrontera Bioscience GmbH, Hemmelrather Weg 201, 51377 Leverkusen, Germany.
authors: Mirella
authors: M
authors: Gwarek
authors: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany. Electronic address: xinran.zhu@ruhr-uni-bochum.de.
authors: Xin-Ran
authors: XR
authors: Zhu
authors: Biofrontera Bioscience GmbH, Hemmelrather Weg 201, 51377 Leverkusen, Germany; Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors: Hermann
authors: H
authors: Lübbert
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D013876:Thiophenes / Q000494:pharmacology; D013892:Thioxanthenes / Q000378:metabolism / Q000494:pharmacology*; D014966:Xanthenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; C000603102:4-(thioxanthene-9-ylidene)piperidine; D001798:Blood Proteins; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D013876:Thiophenes; D013892:Thioxanthenes; D014966:Xanthenes; C015068:1-(3-chlorophenyl)piperazine
keywords: 5-HT(2B) receptor; Antagonist BF-1