Synthesis and muscarinic activity of novel aniline derivatives with a 1-azabicyclo[3.3.0]octane moiety.
In order to develop drugs effective against Alzheimer's disease, we synthesized a series of aniline derivatives having a characteristic cyclic amine, 1-azabicyclo[3.3.0]octane ring, and evaluated their binding affinity for the central muscarinic cholinergic receptor. Among these compounds which showed high affinity to the M1 receptor, N-[2-(1-Azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline (9f fumarate, SK-946) showed the highest affinity. The ability of this compound to improve cognitive function was assessed using the passive avoidance test in scopolamine-induced dementia mice. Some anilines with a 1-azabicyclo[3.3.1]nonane ring were also synthesized by the ring expansion of the 1-azabicyclo[3.3.0]octane ring, and showed a high affinity for the central muscarinic cholinergic receptor.
Suzuki
T
T
Drug Discovery Research Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan.
Oka
M
M
Maeda
K
K
Furusawa
K
K
Uesaka
H
H
Kataoka
T
T
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism