501901-98-0Relevant articles and documents
(R)-3′-(3-methylbenzo[6]thiophen-5-yl)spiro[1-azabicyclo[2,2,2] octane-3,5′-oxazolidin]-2′-one, a novel and potent α7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties
Tatsumi, Ryo,Fujio, Masakazu,Takanashi, Shin-Ichi,Numata, Atsushi,Katayama, Jiro,Satoh, Hiroyuki,Shiigi, Yasuyuki,Maeda, Jun-Ichi,Kuriyama, Makoto,Horikawa, Takashi,Murozono, Takahiro,Hashimoto, Kenji,Tanaka, Hiroshi
, p. 4374 - 4383 (2007/10/03)
Recent studies have suggested that the α7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (5)-spiro[1-azabicyclo[2.2.2]octane-3,5′-oxazolidin]-2′-ones bearing various bicyclic moieties to discover novel ′7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent α7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (Ki = 3 nmol/L) toward the α7 receptor but also showed agonistic activity even at a concentration of 0.1 μmol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the α7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.
