期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 71, 期 -, 页码 237-249出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.10.066
关键词
Tetralone; Tetralol; Synthesis; Dopamine; Serotonin; Antipsychotic
资金
- Spanish Ministerio de Educacion, Cultura y Deporte [SAF2009-13609-C04]
- Xunta de Galicia [INCITE09 203 184PR]
- Ministerio de Educacion, Cultura y Deporte
A series of novel alpha-tetralone and a-tetralol derivatives was synthesized, and their binding affinities for 5-HT2A and D-2 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-HT2A affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pK(i) value for 5-HT2A higher than 8.3 and good binding affinities for D-2 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-HT2A/D-2 dual ligands. Compound 11 shows the best profile with good pK(i) values for 5-HT2A and D-2 receptors leading to a Meltzer's ratio characteristic of a typical antipsychotic behaviour. These three compounds behaved as competitive antagonists of both 5-HT2A and D-2 receptors, and might be promising pharmacological tools for the investigation of the dual function of the 5HT(2A)-D-2 ligands. (C) 2013 Elsevier Masson SAS. All rights reserved.
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