Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of α7 nicotinic acetylcholine receptors.

@article{Hogenkamp2013DesignSA,
  title={Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of $\alpha$7 nicotinic acetylcholine receptors.},
  author={Derk J. Hogenkamp and Thomas A Ford-Hutchinson and Wen-Yen Li and Edward R. Whittemore and Ryan F. Yoshimura and Minhtam B. Tran and Timothy B C Johnstone and Gavin D. Bascom and Hannah Rollins and L Lu and Kelvin W. Gee},
  journal={Journal of medicinal chemistry},
  year={2013},
  volume={56 21},
  pages={
          8352-65
        }
}
A series of novel arylpyrid-3-ylmethanones (7a-aa) were designed as modulators of α7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human α7 nAChRs expressed in Xenopus ooctyes. Structure-activity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC5 response of 1200% and EC50 = 0.18 μM. Compound 7z was active in… 
1,3-diphenylpropan-1-ones as allosteric modulators of α7 nACh receptors with analgesic and antioxidant properties.
TLDR
1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of nAChR-mediated diseases and showed antinociceptive effects in a model of inflammatory pain.
Chemical conversion of nicotinamide into type I positive allosteric modulator of α7 nAChRs.
Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery
  • A. Terry, P. Callahan
  • Biology, Psychology
    Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco
  • 2019
TLDR
The studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.
Nicotinic Acetylcholine Receptor Modulators
TLDR
The large majority of drug development of nAChR ligands for schizophrenia have been α7 agonists and partial agonists, and therapeutics in late-stage development may constitute a breakthrough for the treatment of schizophrenia with safe and effective medicines.
Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders.
Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury
TLDR
It is demonstrated that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period, and may be a novel therapeutic to improve cognition after TBO.
...
1
2
...

References

SHOWING 1-10 OF 56 REFERENCES
Old and New Pharmacology: Positive Allosteric Modulation of the α7 Nicotinic Acetylcholine Receptor by the 5-Hydroxytryptamine2B/C Receptor Antagonist SB-206553 (3,5-Dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b′]di pyrrole-1(2H)-carboxamide)
TLDR
SB-206553 reversed an MK-801 (dizocilpine maleate)-induced deficit in the prepulse inhibition of acoustic startle response, an effect attenuated in the presence of MLA, and provided further evidence in support of the potential therapeutic utility of α7 nAChR PAMs in schizophrenia.
Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor
The α7 nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimer's disease, Parkinson's disease, and
Distinct Profiles of α7 nAChR Positive Allosteric Modulation Revealed by Structurally Diverse Chemotypes
TLDR
Two distinct α7 PAM profiles are revealed, which could offer unique opportunities for modulating α7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.
A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor: In Vitro and In Vivo Characterization
TLDR
Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia, and has the potential to treat psychiatric and neurological disorders.
Enaminone amides as novel orally active GABAA receptor modulators.
TLDR
Structural-activity relationship (SAR) studies resulted in the synthesis of the c-Bu amide 16h with an in vitro potency of 7 nM based on inhibition of [35S]TBPS binding, which was an orally active anxiolytic in the mouse light-dark paradigm.
Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators
TLDR
A selective α7 nAChR-positive allosteric modulator (PAM) from a library of GABAA receptor PAMs is generated, which corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement in rodent models.
Modulation of the chloride ionophore by benzodiazepine receptor ligands: influence of gamma-aminobutyric acid and ligand efficacy.
TLDR
Examination of the kinetics of [35S]TBPS binding suggested the presence of slowly and rapidly dissociating components, and differential effects of GABA-positive versus GABA-negative ligands on [ 35S] TBPS binding and the modulatory effect of GABA provide further evidence to suggest that [35 S]TB PS labels a site near the chloride ionophore linked to the GABA-BZ receptor complex.
2-Oxo-1,8-naphthyridine-3-carboxylic acid derivatives with potent gastric antisecretory properties.
TLDR
The syntheses of 2-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having potent gastric antisecretory properties in the pyloric-ligated (Shay) rat model are described and inhibitory activity in food-stimulated acid secretion in the Pavlov-pouch, conscious dog is shown.
3 alpha-Hydroxy-3 beta-trifluoromethyl-5 alpha-pregnan-20-one (Co 2-1970): a partial agonist at the neuroactive steroid site of the gamma-aminobutyric acidA receptor.
TLDR
Co 2-1970 is a partial agonist at the neuroactive steroid site associated with GABAA receptors, suggesting that it haspartial agonist properties at the steroid site.
...
1
2
3
4
5
...