title: Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/serotonin ligands.
abstract: A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-HT(2A) and D₂ receptors, the most important targets implicated in the anti-schizophrenia drug action, were evaluated to elucidate how substitutions in the aromatic ring of the pharmacophore affect to the affinity or selectivity for these receptors. The replacement of the H-7 in the tetrahydronaphthalene system by an amino group resulted in privileged 5-HT(2A) affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pK(i) value for 5-HT(2A) higher than 8.3 and good binding affinities for D₂ receptor leading to a Meltzer's ratio characteristic of an atypical antipsychotic profile. Additionally, a small collection of 3-aminomethyltetralone derivatives was prepared and examined here for their affinities and selectivities as 5-HT(2A)/D₂ dual ligands. Compound 11 shows the best profile with good pKi values for 5-HT(2A) and D₂ receptors leading to a Meltzer's ratio characteristic of a typical antipsychotic behaviour. These three compounds behaved as competitive antagonists of both 5-HT(2A) and D₂ receptors, and might be promising pharmacological tools for the investigation of the dual function of the 5HT(2A)-D₂ ligands.
authors: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain. Electronic address: laura.carro@usc.es.
authors: Laura
authors: L
authors: Carro
authors: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain. Electronic address: maria.torrado@usc.es.
authors: María
authors: M
authors: Torrado
authors: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain. Electronic address: enrique.ravina@usc.es.
authors: Enrique
authors: E
authors: Raviña
authors: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain. Electronic address: christianf.masaguer@usc.es.
authors: Christian F
authors: CF
authors: Masaguer
authors: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain. Electronic address: sonia.lage@rai.usc.es.
authors: Sonia
authors: S
authors: Lage
authors: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain. Electronic address: pepo.brea@usc.es.
authors: José
authors: J
authors: Brea
authors: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain. Electronic address: mabel.loza@usc.es.
authors: María I
authors: MI
authors: Loza
mesh_terms: D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D044024:Tetralones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058830:Serotonin 5-HT2 Receptor Antagonists; D044024:Tetralones; D012701:Serotonin; C019106:tetralol; D004298:Dopamine
keywords: Antipsychotic; Dopamine; Serotonin; Synthesis; Tetralol; Tetralone