EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors

Prickaerts, Jos; Goethem, Nick P. van; Chesworth, Richard; Shapiro, Gideon; Boess, Frank; Methfessel, Christoph; Reneerkens, Olga A.H.; Flood, Dorothy G.; Hilt, Dana; Gawryl, Maria S.; Bertrand, Sonia; Bertrand, Daniel; König, Gerhard

doi:10.1016/j.neuropharm.2011.10.024

Cited by 199 publications

(194 citation statements)

References 38 publications

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“…As has been shown previously, in some conditions, low concentrations of agonist can yield an unusual potentiation of ACh-evoked currents at a7 nAChRs (Wallace et al, 2010;Prickaerts et al, 2012). Thus, we tested if this protocol of irregular stimulation of the receptor would allow us to detect a possible interaction of the cotinine isomers with nAChRs.…”

Section: R-(1) and S-(2) Isomers Of Cotinine Enhance The Achevoked Cusupporting

confidence: 53%

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

Terry

Callahan

Bertrand

2014

J Pharmacol Exp Ther

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The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in some model systems; however, the mechanism of these effects is unknown. In this study, both the R-(1) and S-(2) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human a4b2 and a7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at a4b2 or a7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at a7 nAChRs exposed to 1.0 mM R-(1)-or S-(2)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(1)-or S-(2)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer's disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-b-erythroidine, indicating that both a7 and a4b2 nAChRs contribute to the response. These results indicate that cotinine may sensitize a7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders.

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Section: R-(1) and S-(2) Isomers Of Cotinine Enhance The Achevoked Cusupporting

confidence: 53%

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

Terry

Callahan

Bertrand

2014

J Pharmacol Exp Ther

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“…The finding that at low concentrations, a7 nAChR agonists can increase the amplitude of ACh responses at a7 nAChRs expressed in cells has suggested that a7 nAChR agonists in vivo may similarly be acting in conjunction with the native ligand ACh. In vitro, the effect of a7 nAChR agonists on enhancing the activity of ACh has been termed "priming" (Quik et al, 1997;Papke et al, 2011b) and has also been observed with high-affinity a7 nAChR agonists Prickaerts et al, 2012). Although the underlying mechanisms of priming have not been fully revealed, a suggested mechanism has been described for the neuromuscular junction nAChR, in which priming may represent the stabilization of receptor conformations by ACh that are more easily activated by subsequent exposure to another molecule of ACh (Mukhtasimova et al, 2009).…”

Section: E Effects Of Chronic Exposure Of A7 Nicotinic Acetylcholinementioning

confidence: 99%

“…This analog, PHA- (Acker et al, 2008), advanced into Phase 1 clinical studies. Recently, encenicline, a potent quinuclidine amide analog reported by FORUM (formerly EnVivo, Waltham, MA), demonstrated partial agonist activity at a7 nAChRs (K i = 10 nM) and antagonist activity at 5-HT 3 receptors (IC 50 , 10 nM) (Prickaerts et al, 2012). Encenicline demonstrated preclinical procognitive effects in rat NOR, as well as efficacy in Phase 1 and Phase 2 trials in normal volunteers and patients with schizophrenia (Barbier et al, 2015;Keefe et al, 2015), and is now in Phase 3 trials for treatment of cognitive impairment in schizophrenia and Alzheimer's disease.…”

Section: Gts-21mentioning

confidence: 99%

“…Preclinical studies have demonstrated the efficacy of several a7 nAChR agonists in an N40 sensory gating model (Hashimoto et al, 2005;Simosky et al, 2008;Wildeboer-Andrud and Stevens, 2011), in particular ABT-107 (Radek et al, 2012). Other molecules such as TC-5619, SSR-180711, A-582941, or encenicline also demonstrated efficacy in cognitive models (Pichat et al, 2007;Tietje et al, 2008;Mazurov et al, 2012;Prickaerts et al, 2012). Although application of an a7 nAChR agonist alone was ineffective in a DBA/2 mouse model of sensorimotor gating (prepulse inhibition), it increased the effects of haloperidol or risperidone (Kohlhaas et al, 2012).…”

Section: B Schizophreniamentioning

confidence: 99%

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Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…Here, adverse effects as seen with a high dose of the agonist, presumably through interaction with ganglionic a3b4 nAChRs, could be avoided using a lower agonist dose in combination with NS9283 and still provide the same or even stronger analgesic effects. The same concept has also been demonstrated with donepezil, which is dose-limited by its adverse effects, in combination with two different a7 PAMs in cognition paradigms [100,101]. Also, based on binding of NS9283 and NS206 in two different domains of the a4b2 receptor as well as an additive effect of the two compounds, it was recently suggested that NS206, or compounds with an equivalent binding profile, may serve as an add-on therapy to galantamine in AD, which similar to NS9283 also binds in an extracellular domain [82].…”

Section: Clinical Opportunities and Concerns With A4b2 Pamsmentioning

confidence: 66%

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

Grupe

Grunnet

Bastlund

et al. 2014

Basic Clin Pharma Tox

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Abstract:The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric a4b2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the a4b2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the a4b2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the a4b2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of a4b2 nAChRs as key regulators of fast synaptic transmission.For decades, the a4b2 subtype of nicotinic acetylcholine (ACh) receptors (nAChRs) has been extensively investigated as a putative drug target in different therapeutic areas. Being widely involved in central neurotransmission as well as implicated in various pathophysiological states, much research has been aimed at developing pharmacological ligands targeting this subtype as a treatment approach in both psychiatric and neurodegenerative diseases [1][2][3][4][5]. The ligand class having received most attention within nAChR drug development aimed at diseases of the central nervous system (CNS) is subtype-selective agonists [1]. However, the success of these efforts must so far be considered limited as the only a4b2 ligands currently approved for medical use are the partial a4b2 nAChR agonists, varenicline and cytisine [6], which are used as smoking cessation aids. This has set off a drug hunt for novel types of modulators targeting the a4b2 nAChR as well as other subtypes of the nAChR family, where the focus has switched from agonists to positive allosteric modulators (PAMs) of the recepto...

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EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors

Cited by 199 publications

References 38 publications

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

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