Synthesis and binding profile of constrained analogues of N -[4-(4-arylpiperazin-1-yl)butyl]-3-methoxybenzamides, a class of potent dopamine D3 receptor ligands

Abstract

We recently reported on a series of N-[4-(4-arylpiperazin-1-yl)butyl]-3-methoxybenzamides, endowed with high affinity for dopamine D3 receptors, but lacking of selectivity over D4, D2, 5-HT1A, and α1-receptors. To improve the D3-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-CH3O-Ph, 4-Cl-Ph, 2,3-di-CH3-Ph) were tested in-vitro for their binding affinity for D3, D4, D2, 5-HT1A, and α1-receptors. The trans- derivatives were found to be more potent at D3 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 D3-receptor affinity (Ki = 0.18 nm) and a relevant selectivity over D4, D2, 5-HT1A, and α1-receptors (>200-fold). This compound was characterized as a full agonist at D3 receptor when tested in the Eu-GTP binding assay.