Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 25, Issue 16, Pages 3184-3188Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.05.094
Keywords
Acetylcholine; Nicotine; Nicotinic receptor; alpha 7; Benzamide; Fluorobenzamide; Zacopride; Xenopus oocytes
Categories
Funding
- Region des Pays de la Loire in the framework of the ECRIN 'Paris Scientifiques' [Rat alpha7 nAChR, RIC-3]
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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 alpha 7 nicotinic acetylcholine receptor expressed in Xenopus oocytes. We found that LMA10203 was a partial agonist of alpha 7 receptor with a pEC(50) value of 4.25 +/- 0.06 mu M whereas LMA10227 and LMA10228 were poorly active on alpha 7 homomeric nicotinic receptor. LMA10227 and LMA10228 were identified as antagonists of acetylcholine-induced currents with IC50 values of 28.4 mu M and 39.3 mu M whereas LMA10203 and zacopride possessed IC50 values of 8.07 mu M and 7.04 mu M, 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 a7 receptor. (C) 2015 Elsevier Ltd. All rights reserved.
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