Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin(7) (5-HT7) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo

• Published in: Journal of medicinal chemistry Vol. 55; no. 14; pp. 6375 - 6380
• Main Authors: Lacivita, Enza, Patarnello, Daniela, Stroth, Nikolas, Caroli, Antonia, Niso, Mauro, Contino, Marialessandra, De Giorgio, Paola, Di Pilato, Pantaleo, Colabufo, Nicola A., Berardi, Francesco, Perrone, Roberto, Svenningsson, Per, Hedlund, Peter B., Leopoldo, Marcello
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 26.07.2012
• Subjects: Animals; Chemistry, Medicinal; Guinea Pigs; HeLa Cells; Humans; Ileum - drug effects; Ileum - metabolism; Life Sciences & Biomedicine; Ligands; Medicin och hälsovetenskap; Models, Molecular; Molecular Weight; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Protein Conformation; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Serotonin - chemistry; Receptors, Serotonin - metabolism; Science & Technology; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - metabolism; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - metabolism; Serotonin Receptor Agonists - pharmacology; Structure-Activity Relationship; Substrate Specificity; ACTIVATION; AFFINITY; N-(1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)-4-ARYL-1-PIPERAZINEHEXANAMIDES; CLONING; AGENTS; DERIVATIVES; EXPRESSION; BRAIN
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm3003679

Here we report the design, synthesis, and 5-HT7 receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT7 affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT7 affinities in the nanomolar range and >100-fold selectivity over 5-HT1A and adrenergic alpha(1) receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (9a) showed 5-HT7 agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT(7)(-)expressing HeLa cells.