(R)-3‘-(3-Methylbenzo[b]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

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.

Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: An overview of preclinical and clinical findings

“…Deteriorating effects of both the α4β2* antagonist DHβE and the α7-specific antagonist methyllycaconitine (MLA) have been reported (Addy et al 2003;Arthur and Levin 2002;Bancroft and Levin 2000;Bettany and Levin 2001;Chan et al 2007;Felix and Levin 1997;Levin et al 2002;Nott and Levin 2006). Conversely, working memory improved after administration of nicotinic agonists (Chan et al 2007;Gatto et al 2004;Levin et al 1999;Lippiello et al 1996;Tatsumi et al 2006). A study with knockout mice substantiates these results further: both β2* and α7 knockouts have been connected to radial arm maze performance (Levin et al 2009).…”

“…Both scopolamine and mecamylamine were found to impair working memory functions of rats and monkeys in maze tasks (Beatty and Bierley 1985;Kay et al 2010;Kobayashi et al 1995;Levin et al 1987;Ohno et al 1993;Okaichi et al 1989;Tatsumi et al 2006;Wirsching et al 1984) and delayed matching tasks (e.g. Granon et al 1995;Spinelli et al 2006).…”

“…Cholinergic influence on working memory in humans and animalsBeatty and Bierley 1985;Kay et al 2010;Okaichi et al 1989;Tatsumi et al 2006;Wirsching et al 1984 …”

Effect of Chirality on Common in Vitro Experiments: An Enantiomeric Pair Analysis

“…Chemical moieties most commonly associated with reversible CYP inhibition are achiral sp 2 hybridized systems characterized by electron rich heterocycles including imidazoles, 48 thiophenes, 49 furan, 50 and pyridines. 51 Binding of the heteroatom lone-pair with the prosthetic iron(III) is commonly invoked as the CYP inhibition mechanism.…”

Nicotinic Acetylcholine Receptor Modulators

“…A derivative of AR-R17779 called W-56203 (12) enhanced cognition in auditory sensory gating and reversed the scopolamine-induced impairment of cognitive performance in an eight-arm radial maze task in rat models [132]. Given its moderate pharmacokinetic profile, W-56203 was reported as a promising drug candidate for the treatment of cognitive impairment associated with neurological disorders.…”