Pharmacological profile of zacopride and new quaternarized fluorobenzamide analogues on mammalian α7 nicotinic acetylcholine receptor

[Display omitted] From quaternarization of quinuclidine enantiomers of 2-fluoro benzamide LMA10203 in dichloromethane, the corresponding N-chloromethyl derivatives LMA10227 and LMA10228 were obtained. Here, we compared the agonist action of known zacopride and its 2-fluoro benzamide analogues, LMA10...

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Published in:Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (16), p.3184-3188
Main Authors: Bourdin, Céline M., Lebreton, Jacques, Mathé-Allainmat, Monique, Thany, Steeve H.
Format: Article
Language:English
Subjects:
Acetylcholine
Acetylcholine - metabolism
alpha7 Nicotinic Acetylcholine Receptor - drug effects
Animals
Benzamide
Benzamides - chemical synthesis
Benzamides - pharmacology
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Dose-Response Relationship, Drug
Female
Fluorobenzamide
Humans
Life Sciences
Nicotine
Nicotine - metabolism
Nicotinic Antagonists - pharmacology
Nicotinic receptor
Oocytes - drug effects
Oocytes - metabolism
Stereoisomerism
Structure-Activity Relationship
Xenopus laevis
Xenopus oocytes
Zacopride
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Summary:[Display omitted] From quaternarization of quinuclidine enantiomers of 2-fluoro benzamide LMA10203 in dichloromethane, the corresponding N-chloromethyl derivatives LMA10227 and LMA10228 were obtained. Here, we compared the agonist action of known zacopride and its 2-fluoro benzamide analogues, LMA10203, LMA10227 and LMA10228 against mammalian homomeric α7 nicotinic acetylcholine receptor expressed in Xenopus oocytes. We found that LMA10203 was a partial agonist of α7 receptor with a pEC50 value of 4.25±0.06μM whereas LMA10227 and LMA10228 were poorly active on α7 homomeric nicotinic receptor. LMA10227 and LMA10228 were identified as antagonists of acetylcholine-induced currents with IC50 values of 28.4μM and 39.3μM whereas LMA10203 and zacopride possessed IC50 values of 8.07μM and 7.04μM, respectively. Moreover, despite their IC50 values, LMA10227 was the most potent inhibitor of nicotine-induced current amplitudes (65.7±2.1% inhibition). LMA10203 and LMA10228 had the same inhibitory effects (26.5±7.5% and 33.2±4.1%, respectively), whereas zacopride had no significant inhibitory effect (4.37±4%) on nicotine-induced responses. Our results revealed different pharmacological properties between the four compounds on acetylcholine and nicotine currents. The mode of action of benzamide compounds may need to be reinterpreted with respect to the potential role of α7 receptor.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.05.094