title: Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies.
abstract: We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4β2 nicotinic receptor (up to 1 μM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported.
authors.affiliation: Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ouach
authors.affiliation: Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Pin
authors.affiliation: Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bertrand
authors.affiliation: UMR Inserm U930, Universite François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Johnny
authors.initials: J
authors.lastname: Vercouillie
authors.affiliation: UMR Inserm U930, Universite François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Zuhal
authors.initials: Z
authors.lastname: Gulhan
authors.affiliation: Laboratoires Cyclopharma, Biopôle Clermont-Limagne, 63360 Saint-Beauzire, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Mothes
authors.affiliation: Laboratoires Cyclopharma, Biopôle Clermont-Limagne, 63360 Saint-Beauzire, France.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Deloye
authors.affiliation: UMR Inserm U930, Universite François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.affiliation: Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Suzenet
authors.affiliation: UMR Inserm U930, Universite François Rabelais de Tours, CHRU de Tours, Tours, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.affiliation: Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France. Electronic address: sylvain.routier@univ-orleans.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D057930:Click Chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000378:metabolism*
chemical_list: D008024:Ligands; D011978:Receptors, Nicotinic; D058831:Serotonin 5-HT3 Receptor Antagonists; D014230:Triazoles; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2
keywords: Alpha 7 nicotinic acetylcholine receptors; In vitro evaluation; Quinuclidine; SAR; Triazole synthesis; Tropane