title: Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α<alpha>1 and 5-HT1A receptors.
abstract: Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α<alpha>1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α<alpha>1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α<alpha>1 or 5-HT1AR ligands.
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchini
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors.forename: Umberto M
authors.initials: UM
authors.lastname: Battisti
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Baraldi
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Prandi
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tait
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sorbi
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
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: Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148 Milano, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pirona
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy. Electronic address: livio.brasili@unimore.it.
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
mesh_terms: D000473:Alkanes / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000473:Alkanes; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D013141:Spiro Compounds; D044282:Receptor, Serotonin, 5-HT1A; C012867:decane
keywords: 1,3-Dioxolane; 5-HT(1A)R; Arylpiperazine derivatives; Structure–affinity/activity relationships; α<alpha>1 receptor