Structure-5-HT/D2 Receptor Affinity Relationship in a New Group of 1-Arylpiperazynylalkyl Derivatives of 8-Dialkylamino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione

Abstract

In our previous papers, we have reported that some 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic, partial agonistic, or antagonistic activity for serotonin 5-HT_1A and dopamine D₂ receptors. In order to examine further the influence of the substituent in the position 8 of the purine moiety and the influence of the xanthine core on the affinity for serotonin 5-HT_1A , 5-HT_2A , 5-HT₆ , 5-HT₇ , and dopamine D₂ receptors, two series of 1-arylpiperazynylalkyl derivatives of 8-amino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for the serotonin 5-HT_1A , 5-HT_2A , 5-HT₆ , 5-HT₇ , and dopamine D₂ receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, the functional assays for the 5-HT_1A and D₂ receptors were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for 5-HT_1A receptors and agonistic, partial agonistic, or antagonistic activity for D₂ receptors. In total, 26 new compounds were synthesized, 20 of which were tested in in vitro binding experiments and 5 were tested in in vitro functional assays.

Keywords: 5-HT1A; D2; LCAPs; Theobromine.