title: Improving selectivity preserving affinity: new piperidine-4-carboxamide derivatives as effective sigma-1-ligands.
abstract: We report the design, synthesis and binding evaluation against σ1 and σ2 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on σ receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a-o were tested to estimate their affinity and selectivity toward σ1 and σ2 receptors. Very high σ1 affinity (Ki = 3.7 nM) and Kiσ2/Kiσ1 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4-chlorobenzyl moiety linked to the piperidine nitrogen atom.
authors.affiliation: Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy. Electronic address: dzampieri@units.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Zampieri
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DI3, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.affiliation: Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Vio
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DI3, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DI3, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy; National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste, Italy. Electronic address: sabrina.pricl@di3.units.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Corrensstrasse 48, 48149 Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Corrensstrasse 48, 48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Mamolo
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000601854:piperidine-4-carboxamide
keywords: Piperidine-4-carboxamide derivatives; Radioligand binding assays; σ-Receptors