(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.
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.
Tatsumi
Ryo
R
Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan.
Fujio
Masakazu
M
Takanashi
Shin-ichi
S
Numata
Atsushi
A
Katayama
Jiro
J
Satoh
Hiroyuki
H
Shiigi
Yasuyuki
Y
Maeda
Jun-ichi
J
Kuriyama
Makoto
M
Horikawa
Takashi
T
Murozono
Takahiro
T
Hashimoto
Kenji
K
Tanaka
Hiroshi
H
D000818:Animals; D001682:Biological Availability; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy; D004298:Dopamine / Q000378:metabolism; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D000882:Haplorhini; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
C513160:3'-(3-methylbenzo(b)thiophen-5-yl)spiro(1-azabicyclo(2.2.2)octane-3,5'-oxazolidin)-2'-one; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D010080:Oxazoles; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004298:Dopamine