Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons

López-Hernández, Gretchen Y.; Placzek, Andon N.; Thinschmidt, Jeffrey S.; Lestage, Pierre; Trocmé-Thibierge, Caryn; Morain, Philippe; Papke, Roger L.

doi:10.1016/j.neuropharm.2007.04.007

Cited by 34 publications

(27 citation statements)

References 49 publications

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“…In vivo studies with ␣7 PAMs have reported no major concerns regarding toxicity, which might suggest that specific factors can prevent overactivation of ␣7 receptors in a physiological context. Even for the temperature-sensitive agent PNU-120596, endogenous potentiating factors may provide a narrow margin of safety for cells expressing high levels of ␣7 receptors, although it should be noted that the peak current of the A7R3HC10 cells is approximately 2-to 3-fold higher than what we have previously reported for ␣7-expressing cells in hippocampal (Lopez-Hernandez et al, 2007) or hypothalamic brain slices (Uteshev et al, 2003). A major concern for considering PAM-based therapeutics is whether a PAM will allow ␣7 receptors to perform their usual functions more effectively or whether it will force ␣7 receptors into playing alternative roles.…”

Section: Discussionmentioning

confidence: 56%

Intrinsically Low Open Probability of α7 Nicotinic Acetylcholine Receptors Can Be Overcome by Positive Allosteric Modulation and Serum Factors Leading to the Generation of Excitotoxic Currents at Physiological Temperatures

et al. 2012

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ABSTRACT␣7 nicotinic acetylcholine receptors (nAChRs) have been a puzzle since their discovery in brain and non-neuronal tissues. Maximal transient probability of an ␣7 nAChR being open with rapid agonist applications is only 0.002. The concentration dependence of ␣7 responses measured from transfected cells and Xenopus laevis oocytes shows the same disparity in potency estimations for peak currents and net charge, despite being studied at 1000-fold different time scales. In both cases the EC 50 was approximately 10-fold lower for net charge than for peak currents. The equivalence of the data obtained at such disparate time scales indicates that desensitization of ␣7 is nearly instantaneous. At high levels of agonist occupancy, the receptor is preferentially converted to a ligand-bound nonconducting state, which can be destabilized by the positive allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-NЈ-(5-methyl-3-isoxazolyl)-urea (PNU-120596). Such currents can be sufficiently large to be cytotoxic to the ␣7-expressing cells. Both the potentiating effect of PNU-120596 and the associated cytotoxicity have a high temperature dependence that can be compensated for by serum factors. Therefore, despite reduced potentiation at body temperatures, use of type II positive allosteric modulators may put cells that naturally express high levels of ␣7 nAChRs, such as neurons in the hippocampus and hypothalamus, at risk. With a low intrinsic open probability and high propensity toward the induction of nonconducting ligand-bound states, it is likely that the well documented regulation of signal transduction pathways by ␣7 nAChRs in cells such as those that regulate inflammation may be independent of ion channel activation and associated with the nonconducting conformational states.

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Section: Discussionmentioning

confidence: 56%

Intrinsically Low Open Probability of α7 Nicotinic Acetylcholine Receptors Can Be Overcome by Positive Allosteric Modulation and Serum Factors Leading to the Generation of Excitotoxic Currents at Physiological Temperatures

et al. 2012

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“…Specifically, (1) MLA did not block S 24795-mediated reduction in A␤ 42 -␣7nAChR association, (2) PNU 282987 only marginally reduced A␤ 42 -␣7nAChR interaction, and (3) S 24795 removed A␤ 42 from A␤ 42 -␣7nAChR complexes with concentrations lower than its apparent affinity for rat brain ␣7nAChRs (4.6 M) (Lopez-Hernandez et al, 2007).…”

Section: Discussionmentioning

confidence: 93%

Dissociating β-Amyloid from α7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes α7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain

Wang¹,

Stucky²,

Liu³

et al. 2009

J. Neurosci.

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“…Several other novel ␣7 nAChR agonists-(2R)-spiro-[1-azabicyclo[2.2.2]octane-3,2(3H)-furo [2,3-b]pyridine]-tartrate (AZD-0328) (Sydserff et al, 2009), 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide (SEN-12333/WAY-317538) (Roncarati et al, 2009) (Feuerbach et al, 2009), 2[2(4-bromophenyl)-2-oxoethyl]-1-methyl-pyridinium chloride (S24795) (Lopez-Hernandez et al, 2007), and N- [2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619) (Hauser et al, 2009)-have been recently described. 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.…”

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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Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons

Cited by 34 publications

References 49 publications

Intrinsically Low Open Probability of α7 Nicotinic Acetylcholine Receptors Can Be Overcome by Positive Allosteric Modulation and Serum Factors Leading to the Generation of Excitotoxic Currents at Physiological Temperatures

Intrinsically Low Open Probability of α7 Nicotinic Acetylcholine Receptors Can Be Overcome by Positive Allosteric Modulation and Serum Factors Leading to the Generation of Excitotoxic Currents at Physiological Temperatures

Dissociating β-Amyloid from α7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes α7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain

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

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