Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the α7 nicotinic acetylcholine receptor: In vitro and in vivo activity

Acker, Brad A.; Jacobsen, E. J.; Rogers, Bruce N.; Wishka, Donn G.; Reitz, Steven C.; Piotrowski, David W.; Myers, Jason K.; Wolfe, Mark L.; Groppi, Vincent E.; Thornburgh, Bruce A.; Tinholt, Paula M.; Walters, Rodney R.; Olson, Beth; Fitzgerald, Laura Rydelek; Staton, Brian A.; Raub, Thomas J.; Krause, Michael; Li, Kai S.; Hoffmann, William E.; Hajós, Mihály; Hurst, Raymond S; Walker, Daniel P.

doi:10.1016/j.bmcl.2008.04.070

Cited by 61 publications

(39 citation statements)

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“…Thus, to improve the selectivity and to diminish functional activity at the hERG channel, an analog of PNU-282987 was designed that demonstrated improved absorption, distribution, metabolism, and excretion properties, reduced hERG activity, as well as an adequate therapeutic index. This analog, PHA- (Acker et al, 2008), advanced into Phase 1 clinical studies. Recently, encenicline, a potent quinuclidine amide analog reported by FORUM (formerly EnVivo, Waltham, MA), demonstrated partial agonist activity at a7 nAChRs (K i = 10 nM) and antagonist activity at 5-HT 3 receptors (IC 50 , 10 nM) (Prickaerts et al, 2012).…”

Section: Gts-21mentioning

confidence: 99%

“…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%

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Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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Section: Gts-21mentioning

confidence: 99%

Section: Gts-21mentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…For example, AR-R17779 was demonstrated to improve learning in a radial-arm maze (Levin et al, 1999), and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide was efficacious in a social recognition memory test (Boess et al, 2007). PNU282987 and PHA-709829 corrected auditory gating deficits produced by amphetamine in rodents (Hajós et al, 2005;Acker et al, 2008), and SSR-180711 reversed a MK-801-induced deficit in retention of episodic memory in rats (Pichat et al, 2007). MEM-3454 (Rezvani et al, 2009) is currently the most advanced ␣7 subtype-selective agonist, and proof-of-concept was recently demonstrated by the positive outcome of a phase II clinical trial for mild-to-moderate AD.…”

mentioning

confidence: 99%

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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“…Selective a 7 agonists have shown excellent in vivo efficacy in the normalization of auditory gating in rats, indicating potential utility in the treatment of the cognitive deficits associated with schizophrenia [48][49][50].…”

Section: The a 7 Receptor And Schizophreniamentioning

confidence: 99%

The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

et al. 2015

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Homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs) have implications in the regulation of cognitive processes such as memory and attention, and have shown promise as a therapeutic target for the treatment of the cognitive deficits associated with schizophrenia. Multiple α7 nAChR agonists have entered human trials; however, unfavorable side effects and pharmacokinetic issues have hindered the development of a clinical α7 nAChR agonist. Currently, EVP-6124 is in phase III clinical trials, and several other α7 nAChR agonists (GTS-21 and AQW051) are in earlier stages of development. This review will summarize the recent advances and failures of α7 nAChR agonists in clinical trials for the treatment of the aforementioned pathology.

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Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the α7 nicotinic acetylcholine receptor: In vitro and in vivo activity

Cited by 61 publications

References 20 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

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

The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

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