Chronobiotic activity of N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]-propanamide. Synthesis and melatonergic pharmacology of fluoren-9-ylethyl amides.
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 1mg/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.
Epperson
James R
JR
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Pkwy, Wallingford, CT 06492-7660, USA. james.epperson@bms.com
Bruce
Marc A
MA
Catt
John D
JD
Deskus
Jeffrey A
JA
Hodges
Donald B
DB
Karageorge
George N
GN
Keavy
Daniel J
DJ
Mahle
Cathy D
CD
Mattson
Ronald J
RJ
Ortiz
Astrid A
AA
Parker
Michael F
MF
Takaki
Katherine S
KS
Watson
Brett T
BT
Joseph P Yevich
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002909:Chronobiology Phenomena / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000737:chemistry*; D006801:Humans; D008550:Melatonin / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011869:Radioligand Assay; D051381:Rats; D044094:Receptors, Melatonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D005449:Fluorenes; D044094:Receptors, Melatonin; D008550:Melatonin