Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α1 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: France 24.11.2014
• Subjects: Alkanes - chemistry; Alkanes - metabolism; Humans; Ligands; Molecular Docking Simulation; Protein Conformation; Receptor, Serotonin, 5-HT1A - chemistry; Receptor, Serotonin, 5-HT1A - metabolism; Receptors, Adrenergic, alpha-1 - chemistry; Receptors, Adrenergic, alpha-1 - metabolism; Spiro Compounds - chemistry; Structure-Activity Relationship; Arylpiperazine derivatives; Structure–affinity/activity relationships; 1,3-Dioxolane; 5-HT(1A)R; α1 receptor
• 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 α1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α1 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 α1 or 5-HT1AR ligands.