Chronobiotic activity of N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]-propanamide. Synthesis and melatonergic pharmacology of fluoren-9-ylethyl amides

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 17; pp. 4601 - 4611
• Main Authors: Epperson, James R., Bruce, Marc A., Catt, John D., Deskus, Jeffrey A., Hodges, Donald B., Karageorge, George N., Keavy, Daniel J., Mahle, Cathy D., Mattson, Ronald J., Ortiz, Astrid A., Parker, Michael F., Takaki, Katherine S., Watson, Brett T., Joseph P.Yevich
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2004; Elsevier Science
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Animals; Binding Sites; Biological and medical sciences; Chronobiology Phenomena - physiology; Chronobiotic; Dose-Response Relationship, Drug; Fluorenes - chemistry; Hormones. Endocrine system; Humans; Medical sciences; Melatonin; Melatonin - metabolism; Mice; NIH 3T3 Cells; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, Melatonin - metabolism; Structure-Activity Relationship; Melatonin; Chronobiotic; Agonist; Rat; Smooth muscle; Chronobiology; Structure activity relation; Running-wheel; Blood vessel; Aromatic compound; Chemical synthesis; Fluorene derivatives; Human; Acute; Rodentia; Coronary artery; Circadian rhythm; Tricyclic compound; Muscle contraction; In vitro; In vivo; Locomotion; Vertebrata; Chronic; Mammalia; Animal; Affinity; Carboxamide; MT2 melatonin receptor; MT1 melatonin receptor; Hormonal receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.07.002

Compound 2b demonstrated full agonism at both human MT 1 and MT 2 receptors and demonstrated chronobiotic activity in both acute and chronic rat models, producing an acute phase advance of 32 min at 1 mg/kg and chronically entraining free-running rats with a mean effective dose of 0.23 mg/kg. This compound was significantly less efficacious than melatonin in constricting human coronary artery. A series of fluoren-9-yl ethyl amides ( 2) were synthesized and evaluated for human melatonin MT 1 and MT 2 receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide ( 2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT 1 and MT 2 receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1 mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.