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

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 24; pp. 7841 - 7852
• Main Authors: Moritomo, Ayako, Yamada, Hiroyoshi, Watanabe, Toshihiro, Itahana, Hirotsune, Akuzawa, Shinobu, Okada, Minoru, Ohta, Mitsuaki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2013; Elsevier
• Subjects: 5-HT2B receptor; 5-HT7 receptor; antagonists; Biochemistry & Molecular Biology; Carbonyl guanidine; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Dual antagonist; Guanidine - analogs & derivatives; Guanidine - chemistry; Guanidine - pharmacology; guinea pigs; Humans; Life Sciences & Biomedicine; Migraine; Molecular Structure; oral administration; Pharmacology & Pharmacy; Physical Sciences; Receptor, Serotonin, 5-HT2B - metabolism; receptors; Receptors, Serotonin - metabolism; Science & Technology; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Structure-Activity Relationship; structure-activity relationships; 5-HT7 receptor; Carbonyl guanidine; Dual antagonist; 5-HT2B receptor; Migraine; SEROTONIN RECEPTOR; PARTITION-COEFFICIENTS; HIGH-AFFINITY; PROTEIN EXTRAVASATION; CLONING; NITRIC-OXIDE; EXPRESSION; BINDING; AQUEOUS SOLUBILITY; 5-HT receptor; 5-HT(2B) receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.10.010

A series of carbonyl guanidine derivatives have been discovered as potent dual 5-HT2B and 5-HT7 receptor antagonists. N-(9-Hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile and showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered. 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=1.8nM and Ki=17.6nM, 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.