title: Pharmacological profile of zacopride and new quaternarized fluorobenzamide analogues on mammalian α7 nicotinic acetylcholine receptor.
abstract: 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 ± 0.06 μM 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 28.4 μM and 39.3 μM whereas LMA10203 and zacopride possessed IC50 values of 8.07 μM and 7.04 μM, 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.
authors.affiliation: Université d'Orléans, Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC) UPRES EA 1207, Rue de Chartres, BP 6759, 45067 Orléans, France; Université d'Angers, RCIM UPRES EA 2647 US INRA 1330, 2 rue Lavoisier, 49045 Angers, France.
authors.forename: Céline M
authors.initials: CM
authors.lastname: Bourdin
authors.affiliation: Université de Nantes, CEISAM UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, Nantes 44322, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Lebreton
authors.affiliation: Université de Nantes, CEISAM UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, Nantes 44322, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Mathé-Allainmat
authors.affiliation: Université d'Orléans, Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC) UPRES EA 1207, Rue de Chartres, BP 6759, 45067 Orléans, France. Electronic address: steeve.thany@univ-orleans.fr.
authors.forename: Steeve H
authors.initials: SH
authors.lastname: Thany
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D009538:Nicotine / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects*
chemical_list: C542690:2-fluorobenzamide; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018733:Nicotinic Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; C055971:zacopride; D000109:Acetylcholine
keywords: Acetylcholine; Benzamide; Fluorobenzamide; Nicotine; Nicotinic receptor; Xenopus oocytes; Zacopride; α7