(R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties

Ryo Tatsumi; Masakazu Fujio; Shin-ichi Takanashi; Atsushi Numata; Jiro Katayama; Hiroyuki Satoh; Yasuyuki Shiigi; Jun-ichi Maeda; Makoto Kuriyama; Takashi Horikawa; Takahiro Murozono; Kenji Hashimoto; Hiroshi Tanaka

doi:10.1021/jm060249c

(R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties

J Med Chem. 2006 Jul 13;49(14):4374-83. doi: 10.1021/jm060249c.

Authors

Ryo Tatsumi¹, Masakazu Fujio, Shin-ichi Takanashi, Atsushi Numata, Jiro Katayama, Hiroyuki Satoh, Yasuyuki Shiigi, Jun-ichi Maeda, Makoto Kuriyama, Takashi Horikawa, Takahiro Murozono, Kenji Hashimoto, Hiroshi Tanaka

Affiliation

¹ Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan.

PMID: 16821797
DOI: 10.1021/jm060249c

Abstract

Recent studies have suggested that the alpha7 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 (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 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 alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

MeSH terms

Animals
Biological Availability
Cerebral Cortex / metabolism
Cognition / drug effects*
Cognition Disorders / drug therapy
Dopamine / metabolism
Evoked Potentials, Auditory / drug effects
Haplorhini
Hippocampus / metabolism
In Vitro Techniques
Male
Maze Learning / drug effects
Membrane Potentials / drug effects
Neurons / drug effects
Neurons / physiology
Nicotinic Agonists / chemical synthesis*
Nicotinic Agonists / pharmacokinetics
Nicotinic Agonists / pharmacology
Nootropic Agents / chemical synthesis*
Nootropic Agents / pharmacokinetics
Nootropic Agents / pharmacology
Oxazoles / chemical synthesis*
Oxazoles / pharmacokinetics
Oxazoles / pharmacology
Patch-Clamp Techniques
Quinuclidines / chemical synthesis*
Quinuclidines / pharmacokinetics
Quinuclidines / pharmacology
Radioligand Assay
Rats
Rats, Wistar
Receptors, Nicotinic / metabolism*
Receptors, Nicotinic / physiology
Stereoisomerism
Structure-Activity Relationship
alpha7 Nicotinic Acetylcholine Receptor

Substances

3'-(3-methylbenzo(b)thiophen-5-yl)spiro(1-azabicyclo(2.2.2)octane-3,5'-oxazolidin)-2'-one
Chrna7 protein, rat
Nicotinic Agonists
Nootropic Agents
Oxazoles
Quinuclidines
Receptors, Nicotinic
alpha7 Nicotinic Acetylcholine Receptor
Dopamine