Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/serotonin ligands

• A series of α-tetralone and α-tetralol derivatives was synthesized.
• SARs of this class of compounds as 5-HT2A/D2 ligands were studied.
• An amino substituent in position-7 facilitated binding affinities.
• Compounds 25 and 36 were found to be the most promising 5-HT2A/D2 ligands.

A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-HT2A 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-HT2A affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pKi value for 5-HT2A 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-HT2A/D2 dual ligands. Compound 11 shows the best profile with good pKi values for 5-HT2A 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-HT2A and D2 receptors, and might be promising pharmacological tools for the investigation of the dual function of the 5HT2A-D2 ligands.

Figure optionsDownload as PowerPoint slide