Effect of R3487/MEM3454, a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats

Rezvani, Amir H.; Kholdebarin, Ehsan; Brucato, Frederic H.; Callahan, Patrick M.; Lowe, David; Levin, Edward D.

doi:10.1016/j.pnpbp.2008.11.018

Cited by 93 publications

(69 citation statements)

References 40 publications

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“…These data suggest that acute activation of the ␣7nAChR is sufficient to produce procognitive effects and is similar to previous reports with other selective ␣7nAChR agonists (Bitner et al, 2007;Pichat et al, 2007). In addition, the RG3487-mediated improvement in episodic memory is in alignment with previously published data showing that this compound improves sustained attention after acute administration (Rezvani et al, 2009).…”

Section: Discussionsupporting

confidence: 91%

“…For example, N- [(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) has been reported to improve sustained attention in rodents after acute administration (Rezvani et al, 2009). The ␣7nAChR is characterized primarily by its high permeability to calcium ions and its rapid desensitization upon agonist binding (Séguéla et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Wallace¹,

Callahan²,

Tehim³

et al. 2010

J Pharmacol Exp Ther

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111

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Neuronal nicotinic ␣7 acetylcholine receptors (␣7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at ␣7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human ␣7nAChR (K i ϭ 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human ␣7nAChRs with an EC 50 of 0.8 M (oocytes) and 7.7 M (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC 50 ϭ 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: Յ0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent ␣7nAChR partial agonist that improves cognitive performance and sensorimotor gating.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Wallace¹,

Callahan²,

Tehim³

et al. 2010

J Pharmacol Exp Ther

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111

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“…Activation of this system has been particularly involved in the amplification of long-term potentiation (LTP) induction [1][2][3] and, consequently, has been linked to learning and memory consolidation [4][5][6]. Particularly, 7 nicotinic cholinergic receptors (nAChR) have been recently implicated in hippocampal activity [7], memory reconsolidation [8] and sustained attention [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Chronic Infusion of Amyloid-β Peptide and Sustained Attention Altered α7 Nicotinic Receptor Density in the Rat Brain

Viel

Caetano²,

Albuquerque³

et al. 2012

CAR

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2012Chronic infusion of amyloid-peptide and sustained attention altered 7 nicotinic receptor density in the rat brain Current Alzheimer Research, Sharjah, v. 9, n. 10, supl., Part 2, pp. 1210-1220, dec, 2012 Abstract: It is already known that progressive degeneration of cholinergic neurons in brain areas such as the hippocampus and the cortex leads to memory deficits, as observed in Alzheimer's disease. This work verified the effects of the infusion of amyloid-(A ) peptide associated to an attentional rehearsal on the density of 7 nicotinic cholinergic receptor (nAChR) in the brain of male Wistar rats. Animals received intracerebroventricular infusion of A or vehicle (control -C) and their attention was stimulated weekly (Stimulated A group: S-A and Stimulated Control group: SC) or not (NonStimulated A group: N-SA and Non-Stimulated Control group: N-SC), using an active avoidance apparatus. Conditioned avoidance responses (CAR) were registered. Chronic infusion of A caused a 37% reduction in CAR for N-SA . In S-A , this reduction was not observed. At the end, brains were extracted and autoradiography for 7 nAChR was conducted using [125 I]--bungarotoxin. There was an increase in 7 density in hippocampus, cortex and amygdala of SA animals, together with the memory preservation. In recent findings from our lab using mice infused with A and the 7 antagonist methyllycaconitine, and stimulated weekly in the same apparatus, it was observed that memory maintenance was abolished. So, the increase in 7 density in brain areas related to memory might be related to a participation of this receptor in the long-lasting change in synaptic plasticity, which is important to improve and maintain memory consolidation.

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“…Although these compounds have provided considerable insight supporting the involvement of ␣7 nAChRs in cognitive and learning functions, the majority of them have inherent limitations. For example, A-582941 (Bitner et al, 2007), MEM3454 (Rezvani et al, 2009), and AZD-0328 (Sydserff et al, 2009) also exhibit relatively high affinity at 5-HT 3 receptors, complicating interpretation of their pharmacological effects. Likewise, SEN-12333/WAY-317538 is a potent antagonist at H 3 receptors.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

Malysz

Anderson²,

Grønlien³

et al. 2010

J Pharmacol Exp Ther

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Enhancement of ␣7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective ␣7 nAChR agonist, 5- 120596)], the addition of ABT-107 elicited MLA-sensitive ␣7 nAChRmediated Ca 2ϩ signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity ␣7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.

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Effect of R3487/MEM3454, a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats

Cited by 93 publications

References 40 publications

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Chronic Infusion of Amyloid-β Peptide and Sustained Attention Altered α7 Nicotinic Receptor Density in the Rat Brain

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

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Effect of R3487/MEM3454, a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats

Cited by 93 publications

References 40 publications

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Chronic Infusion of Amyloid-&beta; Peptide and Sustained Attention Altered &alpha;7 Nicotinic Receptor Density in the Rat Brain

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

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Chronic Infusion of Amyloid-β Peptide and Sustained Attention Altered α7 Nicotinic Receptor Density in the Rat Brain