title: New antithrombotic 1-phthalazinamines with serotonin antagonistic properties.
abstract: We report nineteen 4-aryl- and 4-arylalkyl-1-phthalazinamines (5-8) which we prepared and tested for antithrombotic properties. All compounds were assayed for their antiplatelet activity in the "Born test" with collagen as inducer of the aggregation. N-[4-(1H-1, 2, 4-triazol-1-yl)butyl]-4-phenyl-1-phthalazin-amine (7 c) was the most potent compound, having an IC(50) of 8 microM. When 5-HT (Serotonin) was used to start aggregation the N-(furan-2-yl-methyl)-4-phenyl-1-pthtalazinamine (8 a) had an IC(50) of 2 microM. In vivo potencies were highly significant. N-[5-(1H-1, 2, 4-triazol-1-yl)pentyl]-4-phenyl-1-phthalazinamine (7 d) inhibited thrombus formation by 12% (P < 0.002) in arterioles and 7% (P < 0.01) in venoles as tested with our laser thrombosis model. For compound 8 a we surprisingly found an antagonism to the 5HT(2A) receptor, which is most likely the mechanism of the inhibition of aggregation by this compound.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Johnsen
authors.forename: Klaus
authors.initials: K
authors.lastname: Rehse
authors.forename: Heinz
authors.initials: H
authors.lastname: Pertz
authors.forename: Johannes Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Erwin
authors.initials: E
authors.lastname: Bischoff
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003094:Collagen / Q000494:pharmacology; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D006162:Guanylate Cyclase; D006801:Humans; D066298:In Vitro Techniques; D007834:Lasers; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010793:Phthalazines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D012701:Serotonin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000071756:Soluble Guanylyl Cyclase; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology
chemical_list: D005343:Fibrinolytic Agents; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D044402:Receptor, Serotonin, 5-HT2A; D018160:Receptors, Cytoplasmic and Nuclear; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D003094:Collagen; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase