Synthesis and structure–activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists. Part 2

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 15; pp. 4323 - 4337
• Main Authors: Moritomo, Ayako, Yamada, Hiroyoshi, Watanabe, Toshihiro, Itahana, Hirotsune, Koga, Yuji, Akuzawa, Shinobu, Okada, Minoru
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2014; Elsevier
• Subjects: 5-HT2B receptor; 5-HT7 receptor; Administration, Oral; Animals; Binding Sites; Biochemistry & Molecular Biology; Body Temperature - drug effects; Carbonyl guanidine; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CHO Cells; Cricetinae; Cricetulus; Docking study; Dual antagonist; Guanidine - analogs & derivatives; Guanidine - chemical synthesis; Guanidine - pharmacokinetics; Guinea Pigs; HEK293 Cells; Humans; Hypothermia, Induced; Life Sciences & Biomedicine; Male; Mice; Migraine; Molecular Docking Simulation; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Protein Structure, Tertiary; Receptor, Serotonin, 5-HT2B - chemistry; Receptor, Serotonin, 5-HT2B - genetics; Receptor, Serotonin, 5-HT2B - metabolism; Receptors, Serotonin - chemistry; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Science & Technology; Serotonin - analogs & derivatives; Serotonin - pharmacology; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacokinetics; Structure-Activity Relationship; 5-HT7 receptor; Docking study; Carbonyl guanidine; Dual antagonist; 5-HT2B receptor; Migraine; SEROTONIN RECEPTOR; ACTIVATION; HIGH-AFFINITY; INHIBITION; PROTEIN EXTRAVASATION; CLONING; NITRIC-OXIDE; EXPRESSION; BINDING; 5-HT receptor; 5-HT(2B) receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.05.027

[Display omitted] 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=4.3nM) and 5-HT7 receptor (Ki=4.3nM) 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 30mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.