The Effect of Carboxamide/Sulfonamide Replacement in Arylpiperazinylalkyl Derivatives on Activity to Serotonin and Dopamine Receptors.

A series of carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1-(2,3-dichlorophenyl)piperazine (2,3-DCPP) analogs were prepared and tested for their affinity to bind to serotonin 5-HT1A /5-HT6 /5-HT7 and dopamine D2 receptors. This chemical modification let us explore the impact of the replacement of the carboxamide by the sulfonamide group on the affinity changes. In both the o-OMe-PhP and 2,3-DCPP series, the relative activities of the carboxamides versus sulfonamides toward the 5-HT1A /5-HT6 /5-HT7 and D2 receptors show similar trends. Varied or similar activities for particular receptors were found for the carboxamides/sulfonamides with p-xylyl spacer, while of the two classes of carboxamides and sulfonamides examined, benzyl derivatives of the sulfonamides displayed the highest serotoninergic affinity, in particular to the 5-HT7 receptors (Ki 8-85 nM). The Ki values revealed that, irrespective of the carboxamide/sulfonamide zone, both p-xylyl and benzyl derivatives had the highest affinity for the dopamine D2 receptor (i.e., 16 out of 24 compounds investigated have an affinity below 100 nM). A molecular modeling study of carboxamide 9a and sulfonamide 9b showed that their binding effects to each of 5-HT1A R and D2 R created binding modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a in complexes with a 5-HT1A R (9aI) and D2 R (9aII) are over 83%, while the respective similarities of sulfonamide 9b structures (9bI/9bII) are only about 40%.