Characterization of the 5-HT₇Receptor. Determination of the Pharmacophore for 5-HT₇Receptor Agonism and CoMFA-Based Modeling of the Agonist Binding Site

Abstract

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.

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

“…(17)). The 4 aligned agonists, together with 3 other less active agents (93,97,98), were then used in CoMFA study. Different combinations of steric and electrostatic fields with a lipophilic potential or logP parameter were analyzed, and it turned out that models with overlapping (a 5-hydroxyl oxygen, the centroid of an adjacent aromatic ring and a protonated nitrogen atom); as to the second, its ligand alignment was guided by the receptor binding site.…”

“…In a study by Vermeulen et al, a pharmacophore model for 5-HT 7 R agonists was based on 20 agents belonging to different classes (indolealkylamines, 2-aminotetralins, arylpiperazines and 138-140) [93]. First, compounds were overlapped by Apollo pharmacophore identifying procedure [94] which, instead of functional groups, fitted their projected interaction points which simulated a specific residue of the receptor binding site.…”

Structural Modifications of N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-piperazinehexanamides: Influence on Lipophilicity and 5-HT7 Receptor Activity. Part III

“…23 Considering the 5-HT 7 receptor agonists, a pharmacophore model has been generated from a set of 20 nonselective agonists. 24 This set included also 5-carboxamidotryptamine (5-CT), which is to date used as reference agonist.…”

Recent progress in 5-HT7receptors: potential treatment of central and peripheral nervous system diseases

“…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 [83].…”

“…The compounds were stated to be potent 5-HT 7 receptor antagonists showing selectivity for the 5-HT 7 receptor over other serotonin receptor subtypes, α 1 -and α 2 -adrenoceptors and dopamine D 2 , hGalanin, opioid and muscarinic receptors. The specified compound, N-(4-benzyl-piperazin-1-ylcarbonyl)-N′-(naphthalen-1-ylmethyl)guanidine (83), is 1 of 91 compounds tested in ligand-binding assays in HEK293 cells. The compound had the highest affinity for the 5-HT 7 receptor subtype and was the most selective, exhibiting K i values of 1690, 43, 10,000, 1.4 and 770 nM for 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 and D2 receptors, respectively [122].…”