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‐HT1AR and D2R created binding modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a in complexes with a 5‐HT1AR (9aI) and D2R (...
Source: Archiv der Pharmazie - Category: Drugs & Pharmacology Authors: Tags: Full Paper Source Type: research