The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction

Abstract

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

“…Recently, the M 1 mAChR allosteric agonist GSK1034702, an isomer of compound 44, has shown efficacy in improving episodic memory in humans in a nicotine abstinence model of cognitive dysfunction. 144 An 8 mg dose of GSK1034702 significantly improved immediate recall (but not delayed recall) following abstinence-induced impairment. Furthermore, in preclinical studies, the potency of GSK1034702 was sensitive to the M 1 mAChR F77I mutation, a mutation that also had a pronounced effect on the efficacy of AC-42 and 77-LH-28-1; suggesting a similar, potentially bitopic, binding mode.…”

The muscarinic system, cognition and schizophrenia

“…It has been reported that these new agents display antipsychotic drug-like qualities Ma et al, 2009), reverse scopolamine-induced memory deficits (Lebois et al, 2010) and potentiate CA1 hippocampal pyramidal cell firing, a physiological response associated with learning and memory (Bradley et al, 2010;Buchanan et al, 2010;Jones et al, 2008). In a pre-clinical human trial, Nathan et al (2013) examined the effects of GSK1034702, a potent M1 receptor allosteric agonist, on alleviating the symptoms of cognitive dysfunction amongst a group of, otherwise healthy, male smokers. Employing a nicotine-abstinence model of cognitive dysfunction, GSK1034702 was found to reduce impairments in information encoding by significantly increasing participants performance on measures of Table 1 Behavioural effects of xanomeline.…”

An investigation of the factors that regulate muscarinic receptor expression in schizophrenia

“…Importantly, clinical and preclinical studies suggest that cortical CHRM1 is important in cognitive functions (Anagnostaras et al, 2003;Nathan et al, 2012). Thus, in this study, we choose to expand our studies on cortical CHRM1 to BA6, a region that has been shown to act in concert with BA9 when cognitive tasks such as attention, working memory, episodic memory retrieval and visual awareness are being undertaken (Naghavi and Nyberg, 2005).…”