PSAB-OFP, a selective α7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor

Broad, Lisa M.; Felthouse, Catherine; Zwart, Ruud; McPhie, Gordon; Pearson, Kathy H.; Craig, Peter J.; Wallace, Louise; Broadmore, Richard J.; Boot, John R.; Keenan, Martine; Baker, Stephen; Sher, Emanuele

doi:10.1016/s0014-2999(02)02273-2

Cited by 30 publications

(25 citation statements)

References 29 publications

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“…In addition, SEN12333 did not activate the ␣3␤2 nAChR, which represents the ganglionic receptor family, but at this receptor it acted as a weak antagonist (selectivity ratio of 4-fold). Despite the relatively high structural homology of ␣7 and 5-HT 3A receptors, SEN12333 did not significantly activate or block this ion channel, which is in contrast to what has been observed for some other ␣7 agonists belonging to different chemotypes (Kem, 2000;Broad et al, 2002;Boess et al, 2007). To further characterize the selectivity of SEN12333, its binding to a wide range of receptors was investigated.…”

Section: Sen12333 a Novel ␣7 Nachr Agonist 465contrasting

confidence: 74%

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Roncarati¹,

Scali²,

Comery³

et al. 2009

J Pharmacol Exp Ther

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The ␣7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of ␣7 nAChR. SEN12333 shows high affinity for the rat ␣7 receptor expressed in GH4C1 cells (K i ϭ 260 nM) and acts as full agonist in functional Ca 2ϩ flux studies (EC 50 ϭ 1.6 M). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC 50 ϭ 12 M). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at ␣3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the ␣7-selective antagonist methyllycaconitine, indicating that it is mediated by ␣7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel ␣7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of ␣7 agonists for treatment of neurodegenerative and cognitive disorders.The family of nicotinic acetylcholine receptors, which comprises 16 different subunits in human (␣1-7, ␣9 -10, ␤1-4, ␦, ε, and ␥) that can form many functional homo-and heteropentameric receptor ion channel combinations, contributes to cholinergic neurotransmission in the nervous system and at the neuromuscular junction. The ␣7 nicotinic acetylcholine receptors (nAChRs) are rapidly desensitizing ligand-gated ion channels that are abundantly expressed in the cerebral cortex and the hippocampus, a limbic structure intimately linked to attention processing and memory formation (Gotti et al., 2006). In the hippocampus, ␣7 nAChRs are present in interneurons and glutamatergic pyramidal neurons, in which they are localized presynaptically in nerve terminals and postsynaptically in dendritic spines and soma. In line with their localization, ␣7 nAChRs modulate neurotransmitter release and are responsible for direct fast excitatory neuroArticle, publication date, and citation information can be found at

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Section: Sen12333 a Novel ␣7 Nachr Agonist 465contrasting

confidence: 74%

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Roncarati¹,

Scali²,

Comery³

et al. 2009

J Pharmacol Exp Ther

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“…Numerous complex quinuclidine derivatives, including AR-R17779, PSAB-OFP and PNU-282987, have been identified as a7-selective agonists (Broad et al, 2002;Hajos et al, 2005;Mullen et al, 2000), suggesting that quinuclidine itself and related simple compounds may also have agonist activity. This hypothesis was tested with single-concentration screens.…”

Section: Sample Analysesmentioning

confidence: 99%

Estimation of both the potency and efficacy of α7 nAChR agonists from single-concentration responses

Papke

2006

Life Sciences

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“…Indeed, no consistent improvements have been reported in unimpaired rats (Mirza and Bright, 2001;Terry et al, 2002). Clear identification of the receptor subtypes underlying the beneficial effects of nicotine is made more onerous by the current lack of truly selective compounds and the difficulties associated with producing nAChR subtype selective drugs (Gotti et al, 2000;Broad et al, 2002). It has therefore been suggested that a combined approach of pharmacological interventions and transgenic animals may help delineate the nAChR subtypes involved (Gotti et al, 2000;Chapman, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

Young

Finlayson

Spratt

et al. 2004

Neuropsychopharmacol

208

174

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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.

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PSAB-OFP, a selective α7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor

Cited by 30 publications

References 29 publications

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Estimation of both the potency and efficacy of α7 nAChR agonists from single-concentration responses

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

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