Synthesis and binding profile of constrained analogs of N-4-(4-ARYLPIPERAZIN-1-YL)BUTYL 3-METHOXYBENZAMIDES, a class of potential dopamine D3 receptor ligands

We recently reported on a series of N-[4-(4-arylpiperazin-1-yl)butyl]-3-methoxybenzamides, endowed with high affinity for dopamine D(3) receptors, but lacking of selectivity over D(4), D(2), 5-HT(1A), and alpha(1)-receptors. To improve the D(3)-receptor affinity and selectivity, without causing a considerable increasing in the lipophilicity, the flexible butyl linker was replaced by a more conformationally constrained cyclohexyl linker. The new cis- and trans-N-[4-(4-aryl-1-piperazinyl)cyclohexyl]-3-methoxybenzamides (Aryl= 2,3-di-Cl-Ph, 2-CH(3)O-Ph, 4-Cl-Ph, 2,3-di-CH(3)-Ph) were tested in-vitro for their binding affinity for D(3), D(4), D(2), 5-HT(1A), and alpha(1)-receptors. The trans- derivatives were found to be more potent at D(3) receptor than the corresponding cis- isomers, but less potent than the opened counterparts. This reflected negatively on the selectivity over the other studied receptors. Derivative trans-N-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]cyclohexyl}-3-methoxybenzamide (trans-7) showed high D(3)-receptor affinity (K(i)=0.18 nM) and a relevant selectivity over D(4), D(2), 5-HT(1A), and alpha(1)-receptors (>200-fold). This compound was characterized as a full agonist at D(3) receptor when tested in the Eu-GTP binding assay.