Discovery ofN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an Agonist of the α7 Nicotinic Acetylcholine Receptor, for the Potential Treatment of Cognitive Deficits in Schizophrenia:  Synthesis and Structure−Activity Relationship

Dg, Wishka; Dp, Walker; Km, Yates; Sc, Reitz; Song, Jia; Jk, Myers; Kl, Olson; Ej, Jacobsen; Ml, Wolfe; Ve, Groppi; Aj, Hanchar; Ba, Thornburgh; La, Cortes-Burgos; Eh, Wong; Ba, Staton; Tj, Raub; Nr, Higdon; Tm, Wall; Rs, Hurst; Rr, Walters; We, Hoffmann; Hajós, Mihály; Franklin, Stanley R.; Carey, Galen; Lh, Gold; Kk, Cook; Sb, Sands; Zhao, Shengchuan; Soglia,; As, Kalgutkar; Sp, Arnerić; Bn, Rogers

doi:10.1021/jm0602413

Cited by 185 publications

(120 citation statements)

References 44 publications

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“…Importantly, although the former characteristic of this drug is in line with many reports on a7 agonists (Arendash et al, 1995;Levin et al, 1999;Meyer et al, 1998;Olincy and Stevens, 2007;Pichat et al, 2007;Timmermann et al, 2007;Wishka et al, 2006), the latter capacity to the best of our knowledge is demonstrated here for the first time. Thus, this study suggests that a7-nAChR (partial) agonists can be viewed as promising targets not only for cognitive impairments in schizophrenia, but for treating the wide spectrum of symptoms in schizophrenia, including positive symptoms.…”

Section: Resultssupporting

confidence: 91%

“…We show that SSR180711 was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal NOS blockade; these models are believed to model cognitive aspects of schizophrenia and the activity here was consistent with previous findings with a7-nAChR agonists (Arendash et al, 1995;Hashimoto et al, 2008;Levin et al, 1999;Meyer et al, 1998;Olincy and Stevens, 2007;Pichat et al, 2007;Timmermann et al, 2007;Wishka et al, 2006). Rather unexpectedly SSR180711 potentiated LI in normal rats and reversed amphetamine-induced LI disruption, two models considered predictive of activity against positive symptoms of schizophrenia (Gray et al, 1991;Kilts, 2001;Lipska, 2004;Lipska and Weinberger, 2000;Moser et al, 2000;Powell and Miyakawa, 2006;Smith et al, 2007;Weiner, 1990Weiner, , 2003 .…”

Section: Discussionsupporting

confidence: 90%

“…a7 agonists have been shown to improve performance in various cognitive tasks in rodents, including one-way active avoidance, 8 or 17-arm radial maze, Morris water maze, object recognition and social recognition (Arendash et al, 1995;Hashimoto et al, 2008;Kem, 2000;Levin et al, 1999;Pichat et al, 2007;Timmermann et al, 2007;Van Kampen et al, 2004;Wishka et al, 2006). The dual effect of SSR180711 exerted on disrupted and persistent LI is particularly remarkable in that in terms of effects on performance, the drug influenced the pre-exposed MK801 and neonatal L-NoArg groups in opposite direction from that of the pre-exposed amphetamine group, namely, improved conditioning in the former and impaired conditioning in the latter.…”

Section: Ssr180711-behavioral and Psychological Profilementioning

confidence: 99%

“…A growing body of data demonstrates that a7-nAChR agonists facilitate cognitive function in a variety of learning and memory tasks in rodents and humans (eg Levin et al, 1999;Olincy and Stevens, 2007). Of particular relevance to attentional and sensory gating deficits in schizophrenia (Adler et al, 1998;Heinrichs, 2005;Lubow, 2005), a7-nAChR agonists alleviate both types of deficits in humans and animals Olincy et al, 2006;Timmermann et al, 2007;Wishka et al, 2006). A role for the a7-nAChR in these processes is supported by findings that a7-nAChR knock-out mice show attentional and gating impairments (Adams et al, 2008;Hoyle et al, 2006;Young et al, 2004Young et al, , 2007.…”

Section: Introductionmentioning

confidence: 97%

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Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

Barak

Arad

Levie

et al. 2009

Neuropsychopharmacol

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Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of a7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective a7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously nonreinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with a7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in nodrug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Ssr180711-behavioral and Psychological Profilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

Barak

Arad

Levie

et al. 2009

Neuropsychopharmacol

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“…613) also at Pfizer, Inc.. The second compound demonstrates reversal of amphetamine-induced N40 gating deficit in anesthetized rats and improves the ability to discriminate between familiar and novel objects [121]. Targacept, Inc. has an (E)-Nmethyl-5 (3-pyridinyl)-4-penten-2-amine and Pharmacia & Upjohn Company has a substituted-heteraryl-7-aza[2.2.1]bicycloheptane.…”

Section: Dmxba As a Prototype Drugmentioning

confidence: 99%

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

125

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Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

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Cholinergics/Anticholinergics/Muscarinics/Nicotinics

Griffith

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter quickly summarizes the cholinergic nervous system and the structures of muscarinic and nicotinic receptors. The structure–activity relationships of muscarinic agonists and antagonists are discussed with reference to attempts to develop of drugs selective for one of the five muscarinic receptors, both agonist and antagonists. The structure–activity relationships of agonists and antagonists of nicotinic receptors are presented with initial concentration on the neuronal nicotinic receptors and ending with neuromuscular blockers used in surgery.

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Discovery ofN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an Agonist of the α7 Nicotinic Acetylcholine Receptor, for the Potential Treatment of Cognitive Deficits in Schizophrenia: Synthesis and Structure−Activity Relationship

Cited by 185 publications

References 44 publications

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Cholinergics/Anticholinergics/Muscarinics/Nicotinics

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