ABSTRACT
A series of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active 5-HT7 receptor. Effects on basal adenylate cyclase activity were measured using HEK-293 cells expressing the rat 5-HT7. All ligands produced a decrease of adenylate cyclase activity, indicative of their inverse agonism. Additionally, computational studies with a set of 22 inverse agonists, including these novel inverse agonists and inverse agonists known from literature, resulted in a pharmacophore model and a CoMFA model (R2 = 0.97, SE = 0.18). Docking of inverse agonists at the binding site of a model of the helical parts of the 5-HT7 receptor, based on the alpha carbon template for 7-TM GPCRs, revealed interesting molecular interactions and a possible explanation for observed structure-activity relationships.
Subject(s)
Isoquinolines/chemical synthesis , Piperazines/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Sulfonamides/chemical synthesis , Adenylyl Cyclase Inhibitors , Animals , Binding Sites , Cell Line , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Ligands , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Quantitative Structure-Activity Relationship , Radioligand Assay , Rats , Receptors, Serotonin/chemistry , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
On the basis of a set of 20 diverse 5-HT(7) receptor agonists, the pharmacophore for 5-HT(7) receptor agonism was determined. Additionally two CoMFA models were developed, based on different alignments of the agonists. Both models show good correlations between experimental and predictive pK(i) values and show a high degree of similarity. The CoMFA fields were subsequently used to map the agonist binding site of the model of the 5-HT(7) receptor. Important roles in ligand binding are attributed to Asp162 of TM3 (interaction with a protonated nitrogen), and Thr244 of TM5 (interaction with a substituent at an aromatic moiety). Amino acid residues of the aromatic cluster of TM6 are hypothesized to play an important role in ligand binding as pi-pi stacking moieties. Agonists missing a hydrogen-bond-accepting moiety, but possessing an aromatic substituent instead, seem to bind the receptor with high affinity as well by occupying a lipophilic pocket hosted by residues of TM5 and TM6.