title: Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives.
abstract: Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchini
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Umberto Maria
authors.initials: UM
authors.lastname: Battisti
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Prandi
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tait
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Borsari
authors.affiliation: Dipartimento di Farmacia, Scuola di Scienze Mediche e Farmaceutiche, Università di Genova, Viale Benedetto XV n.3, 16132 Genova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.affiliation: Dipartimento di Farmacia, Scuola di Scienze Mediche e Farmaceutiche, Università di Genova, Viale Benedetto XV n.3, 16132 Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148 Milano, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cilia
authors.affiliation: Dipartimento di Scienze del Farmaco, Sezione di Chimica Farmaceutica, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.affiliation: Dipartimento di Scienze del Farmaco, Sezione di Chimica Farmaceutica, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.affiliation: Dipartimento di Scienze del Farmaco, Sezione di Farmacologia e Tossicologia, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Aricò
authors.affiliation: Dipartimento di Scienze del Farmaco, Sezione di Farmacologia e Tossicologia, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy. Electronic address: livio.brasili@unimore.it.
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004148:Dioxolanes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D004148:Dioxolanes; D008024:Ligands; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D009020:Morphine
keywords: 1,3-Dioxolane; Piperazine; Piperidine; Receptor-mediated analgesia; Sigma receptors ligands; Sigma-1; Sigma-2