title: (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.
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.
authors.affiliation: Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Tatsumi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujio
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Takanashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Numata
authors.forename: Jiro
authors.initials: J
authors.lastname: Katayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Satoh
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shiigi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Maeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuriyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Horikawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murozono
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: 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
chemical_list: 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