Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D₃ receptor ligands

A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D₂ and D₃ receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D₃ receptors and moderate selectivity for the dopamine D₃ versus D₂ receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D₂ and D₃ receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D₄ and serotonin 5-HT_1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D₂ and D₃ receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D₃ receptors.