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

Abstract

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

Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

“…For example, the interaction with S5.42, which was considered as a polar and core contact [48,56], caused stabilization of the L-R complex. Contact with N7.39, which was often engaged in ligand binding, being either an acceptor of hydrogen bond [22,24] or forming dipoledipole interaction [48], based on the FMO calculations is a highly attractive interaction. Comparison between serotonin receptorsa case study for ligand 1 For ligand 1, the in vitro activities towards the studied receptors are known ( Fig.…”

“…After all, this contact is observed both in 5-HT 1B and 5-HT 2B crystals [53][54][55] and is mentioned in many modeling studies for various serotonin receptors [11,23,[45][46][47][48][49][50][51]. Considering, for example, the 5-HT 1A receptor (Table 3), docking studies indicated a specific π-π or π-CH hydrophobic interaction [48,56], while optimization of the binding site using the ONIOM method even showed the possibility to form hydrogen bonding to the ligand [22]. This phenomenon, however, can be explained in the context of the adjacent salt bridge with D3.32, which is the anchor point of the ligand, while the repulsive effect may be one of the elements of signal transduction in the receptor, i.e., the interaction causing the change in protein conformation.…”

“…The pilot series of an active to 5-HT 1A receptor, long-chain arylpiperazine derivatives (Table 1), were used for the energy characterization of 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors orthosteric binding site. The affinity of the compounds was evaluated in vitro by radioligand binding experiments as described previously [22]. Selected ligands belong to a very popular and widely studied class of compounds for these pharmacological targets [22][23][24][25].…”

“…The affinity of the compounds was evaluated in vitro by radioligand binding experiments as described previously [22]. Selected ligands belong to a very popular and widely studied class of compounds for these pharmacological targets [22][23][24][25]. The calculation scheme was as follows: molecular docking, ONIOM optimization, and single-point energy calculation with FMO-EDA method.…”

Pharmacophore Based Virtual Screening and Docking of Different Aryl Sulfonamide Derivatives of 5HT7R Antagonist

“…Pharmacophore alignment and scoring engine (PHASE) was used to develop the 3D-QSAR models as a query in searching 3D databases containing "drug-like" small organic molecules and screened against the Asinex Elite synergy database in potency 10 . Unceasing our effort in developing potent 5HT7R antagonists, we have recently done docking studies on the series of compounds [14][15][16][17][18] to obtain a five-point pharmacophore hypothesis AADPR. In order to identify potential hits, the hits obtained were subjected to a rigorous docking process, and drug-like candidates were screened for main interactions with target Human-5HT7 11 .…”