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‐HT 1A /5‐HT 6 /5‐HT 7 and dopamine D 2 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‐HT 1A /5‐HT 6 /5‐HT 7 and D 2 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‐HT 7 receptors ( K i 8–85 nM). The K i values revealed that, irrespective of the carboxamide/sulfonamide zone, both p ‐xylyl and benzyl derivatives had the highest affinity for the dopamine D 2 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‐HT 1A R and D 2 R created binding modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a in complexes with a 5‐HT 1A R ( 9aI ) and D 2 R ( 9aII ) are over 83%, while the respective similarities of sulfonamide 9b structures ( 9bI / 9bII ) are only about 40%.