title: Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT₂B and 5-HT₇ receptor antagonists. Part 2.
abstract: We previously reported that the novel dual 5-HT₂B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT₂B and 5-HT₇ receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT₇), Tyr (Y370:5-HT₂B, Y374:5-HT₇) and aromatic residue (W131:5-HT2B, F158:5-HT₇). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT₂B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT₂A, 5-HT₂C, α₁, D₂ and M₁ receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.
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.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Development, Astellas Pharma Inc., 3-17-1 Hasune, Itabashi-Ku, Tokyo 174-8612, Japan.
authors.forename: Hirotsune
authors.initials: H
authors.lastname: Itahana
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Akuzawa
authors.affiliation: Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi-shi, Ibaraki 318-0001, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019791:Guanidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D007036:Hypothermia, Induced; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D012701:Serotonin; C047087:5-carboxamidotryptamine; D019791:Guanidine
keywords: 5-HT(2B) receptor; 5-HT(7) receptor; Carbonyl guanidine; Docking study; Dual antagonist; Migraine