Structure–affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α 1 and 5-HT1A receptors

• Published in: European journal of medicinal chemistry Vol. 87; pp. 248 - 266
• Main Authors: Franchini, Silvia, Battisti, Umberto M., Baraldi, Annamaria, Prandi, Adolfo, Fossa, Paola, Cichero, Elena, Tait, Annalisa, Sorbi, Claudia, Marucci, Gabriella, Cilia, Antonio, Pirona, Lorenza, Brasili, Livio
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 24.11.2014
• Subjects: 1,3-Dioxolane; 5-HT1AR; Arylpiperazine derivatives; Structure–affinity/activity relationships; α 1 receptor; Arylpiperazine derivatives; Structure–affinity/activity relationships; 1,3-Dioxolane; α 1 receptor; 5-HT1AR
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.09.070

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 1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α 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 1 or 5-HT1AR ligands. [Display omitted] •Compound 1, a selective and potent 5-HT1A ligand, was selected as lead compound.•A new set of arylpiperazine was prepared with a parallel synthetic strategy.•Affinity and activity at 5-HT1A and α1-adrenoceptor subtypes were obtained.•Docking study into 5HT1AR model proved its reliability of the biological data.