(−)-Spiro[1-azabicyclo[2.2.2]octane-3,5‘-oxazolidin-2‘-one], a Conformationally Restricted Analogue of Acetylcholine, Is a Highly Selective Full Agonist at the α7 Nicotinic Acetylcholine Receptor

Mullen, G. B.; Napier, James; Balestra, Michael; DeCory, Thomas R.; Hale, Gregory A.; Macor, John E.; Mack, R. A.; Loch, James T.; Wu, Ed X.; Kover, Alexander; Verhoest, Patrick R.; Sampognaro, Anthony J.; Phillips, Eifion D.; Zhu, Yanyi; Murray, Robert; Griffith, R. C.; Blosser, James C.; Gurley, David; Machulskis, Anthony C.; Zongrone, John; Rosen, and Alan; Gordon, Jack

doi:10.1021/jm000249r

Cited by 135 publications

(102 citation statements)

References 21 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…DMXBA also attenuated the sensory gating deficits observed in rats that were reared in isolation (O'Neill et al, 2003), an animal neuro-developmental model of schizophrenia (Geyer et al, 1993). Furthermore, both DMXBA (Kem, 2000), and the full a7 nAChR agonist AR-R17779 (Mullen et al, 2000), are able to replicate the beneficial effects observed with nicotine on working memory (Felix and Levin, 1997;Levin and Simon, 1998). In contrast, and perhaps somewhat surprisingly, recent studies in rats showed that AR-R17779 had no effect on attention in the 5-CSR task (Grottick and Higgins, 2000;Grottick et al, 2003;Hahn et al, 2003a).…”

Section: Discussionmentioning

confidence: 93%

Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

Young

Finlayson

Spratt

et al. 2004

Neuropsychopharmacol

209

174

View full text Add to dashboard Cite

In humans, nicotine has been shown to improve attention in both normal and impaired individuals. Observations in rats reflect some, but not all aspects of the nicotine-induced improvements in humans. To date these findings have not been replicated in mice. To examine the effect of nicotine on sustained attention in mice, we have established a version of the 5-choice serial reaction-time (5-CSR) task with graded levels of difficulty, based upon spatial displacement and a variable intertrial interval. Using this paradigm, microgram doses of nicotine produced a consistent reduction in the level of omissions and an improvement in proportion correct in normal mice. This improvement in sustained attention was made irrespectively of whether mice had previously received nicotine. In an attempt to elucidate which nicotinic acetylcholine receptor (nAChR) subtype(s) mediate this effect, we examined the performance of a7 nAChR knockout (KO) mice in the 5-CSR task. a7 nAChR KO mice not only acquired the task more slowly than their wild-type littermates, but on attaining asymptotic performance, they exhibited a higher level of omissions. In conclusion, by increasing the level of task difficulty, the performance of mice was maintained at sufficiently low levels to allow a demonstrable improvement in performance upon nicotine administration. Furthermore, as a7 KO mice are clearly impaired in the acquisition and asymptotic performance of this task, the a7 nAChR may be involved in mediating these effects of nicotine.

show abstract

Section: Discussionmentioning

confidence: 93%

Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

Young

Finlayson

Spratt

et al. 2004

Neuropsychopharmacol

209

174

View full text Add to dashboard Cite

show abstract

“…AR-R 17779, an AstraZeneca product, is an acetylcholine analogue with full agonist properties at the α7 nicotinic cholinergic receptor. This compound does not enhance the inhibition of startle in DBA/2 mice [123,124,125] or improve accuracy and speed of response on a five-choice serial reaction time [126,127]. ABT-418, has some agonist properties at the α7 nicotinic cholinergic receptors, but is a less potent agonist than nicotine [128] and restores deficient auditory gating in DBA/2 mice as well as rats with fimbria-fornix lesions, but similar to nicotine, fails to produce continued improvement with a second dose [54].…”

Section: Dmxba As a Prototype Drugmentioning

confidence: 85%

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

Olincy

Stevens

2007

Biochemical Pharmacology

125

View full text Add to dashboard Cite

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

show abstract

“…The steric and electronic requirements of this site are met by structurally diverse classes of compounds as reviewed recently (Toyohara et al, 2010a), and potential ligands originate from for example benzylidene anabasein compounds such as GTS-21 , or the quinuclidine framework such as AR-R-17779, both shown in Fig. 2 (Bodnar et al, 2005;Mazurov et al, 2005;Mullen et al, 2000;Tatsumi et al, 2005). A recently developed highly selective fluorescent α7 nicotinic receptor ligand is restricted to in vitro studies because of its chemical structure (Hone et al, 2010).…”

Section: Eldar Rosenfeld and Anat Keslermentioning

confidence: 99%

Neuroimaging - Clinical Applications

Bright¹

2012

View full text Add to dashboard Cite

(−)-Spiro[1-azabicyclo[2.2.2]octane-3,5‘-oxazolidin-2‘-one], a Conformationally Restricted Analogue of Acetylcholine, Is a Highly Selective Full Agonist at the α7 Nicotinic Acetylcholine Receptor

Cited by 135 publications

References 21 publications

Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

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

Neuroimaging - Clinical Applications

Contact Info

Product

Resources

About