Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship.

@article{Wishka2006DiscoveryON,
  title={Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship.},
  author={D. Wishka and Daniel P. Walker and K. Yates and S. C. Reitz and S. Jia and J. Myers and Kirk L. Olson and E. Jacobsen and M. Wolfe and V. Groppi and A. J. Hanchar and B. Thornburgh and L. Cortes-Burgos and E. Wong and B. Staton and Thomas J. Raub and N. Higdon and T. Wall and R. Hurst and R. R. Walters and W. E. Hoffmann and M. Haj{\'o}s and S. Franklin and G. Carey and L. Gold and K. Cook and S. Sands and S. Zhao and J. Soglia and A. Kalgutkar and S. Arneric and Bruce N. Rogers},
  journal={Journal of medicinal chemistry},
  year={2006},
  volume={49 14},
  pages={
          4425-36
        }
}
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory… Expand
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 alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity.
A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits inExpand
Discovery of (2S,3R)-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]furan-2-carboxamide (TC-5619), a selective α7 nicotinic acetylcholine receptor agonist, for the treatment of cognitive disorders.
TLDR
Compound 7a, as an augmentation therapy to the standard treatment with antipsychotics, demonstrated encouraging results on measures of negative symptoms and cognitive dysfunction in schizophrenia and was well tolerated in a phase II clinical proof of concept trial in patients with schizophrenia. Expand
[3H]A-585539 [(1S,4S)-2,2-Dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a Novel High-Affinity α7 Neuronal Nicotinic Receptor Agonist: Radioligand Binding Characterization to Rat and Human Brain
TLDR
[3H]A-585539 was shown to have excellent binding characteristics in rat and human brain and represents the first high-affinity α7 agonist radioligand with utility in the characterization of this important nAChR subtype that is targeted toward ameliorating cognitive deficits underlying neuropsychiatric and neurodegenerative disorders. Expand
The Novel α7 Nicotinic Acetylcholine Receptor Agonist N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide Improves Working and Recognition Memory in Rodents
TLDR
The hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential is supported. Expand
[H]A-585539 [(1S,4S)-2,2-Dimethyl-5-(6-phenylpyridazin-3-yl)- 5-aza-2-azoniabicyclo[2.2.1]heptane], a Novel High-Affinity 7 Neuronal Nicotinic Receptor Agonist: Radioligand Binding Characterization to Rat and Human Brain
Receptor binding was characterized for [H](1S,4S)-2,2-dimethyl5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane ([H]A-585539), a selective high-affinity 7 nicotinic acetylcholineExpand
Design and Synthesis of a New Series of 4-Heteroarylamino-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure-Activity Relationship.
TLDR
A series of quinuclidine-containing spirooxazolidines demonstrated excellent selectivity for α7 over the highly homologous 5-HT3A receptor, and improved cognition in preclinical rodent models. Expand
Discovery of novel 2-((pyridin-3-yloxy)methyl)piperazines as α7 nicotinic acetylcholine receptor modulators for the treatment of inflammatory disorders.
TLDR
The design, synthesis, and structure-activity relationships support the hypothesis that the anti-inflammatory activity of the α7 nAChR is mediated by a signal transduction pathway that is independent of ion current. Expand
5-(5-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice.
TLDR
Biodistribution studies in mice showed that [(11)C]rac-1 penetrates the blood-brain barrier and specifically labels neuronal α7-nAChRs. Expand
Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel α7 nicotinic acetylcholine receptor agonist/serotonin 5-HT3 receptor antagonist
TLDR
EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia. Expand
N-[5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): a medicinal chemistry effort toward an α7 nicotinic acetylcholine receptor agonist preclinical candidate.
TLDR
A medicinal chemistry effort around previously reported compound 1 led to the identification of 12 a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models. Expand
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