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

Malysz, John; Anderson, David J.; Grønlien, Jens Halvard; Ji, Jianguo; Bunnelle, William H.; Håkerud, Monika; Thorin-Hagene, Kirten; Ween, Hilde; Helfrich, Rosalind; Hu, Min; Gubbins, Earl J.; Gopalakrishnan, Sujatha M.; Puttfarcken, Pamela S.; Briggs, Clark A.; Li, Jinhe; Meyer, Michael D.; Dyhring, Tino; Ahring, Philip K.; Nielsen, Elsebet Ø.; Peters, Dan; Timmermann, Daniel B.; Gopalakrishnan, Murali

doi:10.1124/jpet.110.167072

Cited by 50 publications

(56 citation statements)

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“…However, some of this diversity also led to azabicyclic amines that exhibited activity as ligands for other nAChR subtypes such as the a4b2 nAChR. Several alternate amines were recently published with a7 nAChR activity and include the diazabicyclononanes such as SSR180711 (Biton et al, 2007;Pichat et al, 2007), the octahydropyrrolo [3,4-c]pyrrole A-582941 (Tietje et al, 2008), and the (3R,5R)-1-azabicyclo-[3.2.1]oct-3-yl-carboxamide PHA-709829 (Acker et al, 2008) and ABT-107 (Bitner et al, 2010;Malysz et al, 2010). The selective partial agonist SSR180711A is a 1,4-diazabicyclo[3.2.2]nonane carbamate derivative (K i = 50 nM, EC 50 = 800 nM) active in NOR, Morris water maze, and an MK-801-induced memory deficit model (Pichat et al, 2007).…”

Section: Gts-21mentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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Section: Gts-21mentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…ABT-089 has been rigorously studied as a treatment of cognitive disorders and has been used successfully in patients with Alzheimer's disease and attention deficit disorder, with few unintended side effects Rueter et al, 2004). Bitner et al, 2010] is a selective agonist with high affinity at a7 nAChRs that has been characterized as a cognitive enhancer in animal models of Alzheimer's disease and has low incidence of side effects at varying doses in patients (Bitner et al, 2010;Malysz et al, 2010;Othman et al, 2011). Both ABT-089 and ABT-107 enhance learning in naive animals Bitner et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Activation ofα4β2/α6β2 Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors

Yohn

Turner

Blendy

2014

J Pharmacol Exp Ther

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Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT ); however, treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. It is noteworthy that the selective partial agonists for a4b2, ABT-089 [2-methyl-3-[2(S)-pyrrolidinylmethoxy]pyridine], and a7, ABT-107North Chicago, IL), have not been evaluated as possible therapeutics for nicotine cessation. Therefore, we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that short-term administration of ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and b2-containing nAChRs were measured using [3 H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotinedependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids.

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“…The 5-hydroxytryptamine 2a receptor has been implicated in sensorimotor gating function (Quednow et al, 2009), and ABT-107 has moderate affinity for 5-hydroxytryptamine 2a and receptors. However, this compound is at least 100-fold more selective for ␣7 receptors over every other non-nicotinic receptor examined (Malysz et al, 2010). This, together with the MLA blockade of ABT-107, tends to implicate a nAChR-mediated mechanism rather than any other.…”

Section: Discussionmentioning

confidence: 98%

“…nAChRs of the ␣7 subtype rapidly desensitize upon exposure to agonists, and desensitization has been demonstrated for ABT-107 in hippocampal GABA inhibitory postsynaptic currents in vitro (Malysz et al, 2010). Desensitization of receptors with the 1.0 mol/kg dose of ABT-107 may be one explanation for a lack of in vivo efficacy in the DBA/2 sensory gating model.…”

Section: Discussionmentioning

confidence: 99%

“…A compound that has some of these characteristics is 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107), which has 79% efficacy to activate human recombinant ␣7 receptors and is at least 100-fold selective over non-␣7 nAChR subtypes (Malysz et al, 2010). ABT-107 rapidly desensitizes native ␣7 receptors in rat hippocampal slices as measured by diminishing inward GABAergic inhibitory postsynaptic currents, a characteristic found with other ␣7 agonists (Malysz et al, 2010). ABT-107 produces cognitive efficacy across a variety of behavioral assays and displays a favorable pharmacokinetic profile with a 1:1 or higher brain-to-plasma ratio in mouse (Bitner et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Effects of the Novel α7 Nicotinic Acetylcholine Receptor Agonist ABT-107 on Sensory Gating in DBA/2 Mice: Pharmacodynamic Characterization

Radek¹,

Robb²,

Stevens³

et al. 2012

J Pharmacol Exp Ther

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Nicotinic acetylcholine receptor (nAChR) agonists improve sensory gating deficits in animal models and schizophrenic patients. The aim of this study was to determine whether the novel and selective ␣7 nAChR full agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107) improves sensory gating deficits in DBA/2 mice. Sensory gating was measured by recording hippocampal-evoked potential P20-N40 waves and determining gating test/conditioning (T/C) ratios in a paired auditory stimulus paradigm. ABT-107 at 0.1 mol/kg (average plasma concentration of 1.1 ng/ml) significantly improved sensory gating by lowering T/C ratios during a 30-min period after administration in unanesthetized DBA/2 mice. ABT-107 at 1.0 mol/kg was ineffective at 30 min after administration when average plasma levels were 13.5 ng/ml. However, the 1.0 mol/kg dose was effective 180 min after administration when plasma concentration had fallen to 1.9 ng/ml. ABT-107 (0.1 mol/kg) also improved sensory gating in anesthetized DBA/2 mice pretreated with ␣7 nAChR-desensitizing doses of nicotine (6.2 mol/kg) or ABT-107 (0.1 mol/kg) itself. Moreover, repeated b.i.d. dosing of ABT-107 (0.1 mol/kg) was as efficacious as a single dose. The acute efficacy of ABT-107 (0.1 mol/kg) was blocked by the nAChR antagonist methyllycaconitine, but not by the ␣4␤2 nAChR antagonist dihydro-␤-erythroidine. These studies demonstrate that ABT-107 improves sensory gating through the activation of nAChRs, and efficacy is sustained under conditions of repeated dosing or with prior nAChR activation with nicotine.

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

Cited by 50 publications

References 40 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Activation ofα4β2/α6β2 Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors

Effects of the Novel α7 Nicotinic Acetylcholine Receptor Agonist ABT-107 on Sensory Gating in DBA/2 Mice: Pharmacodynamic Characterization

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

Cited by 50 publications

References 40 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Activation ofα4β2*/α6β2* Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors

Effects of the Novel α7 Nicotinic Acetylcholine Receptor Agonist ABT-107 on Sensory Gating in DBA/2 Mice: Pharmacodynamic Characterization

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Activation ofα4β2/α6β2 Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors