title: Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists.
abstract: To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ayako.moritomo@astellas.com.
authors.forename: Ayako
authors.initials: A
authors.lastname: Moritomo
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hirotsune
authors.initials: H
authors.lastname: Itahana
authors.forename: Shinobu
authors.initials: S
authors.lastname: Akuzawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
mesh_terms: D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D019791:Guanidine
keywords: 5-HT(2B) receptor; 5-HT(7) receptor; Carbonyl guanidine; Dual antagonist; Migraine