Spiro[pyrrolidine-3,3'-oxindoles] and Their Indoline Analogues as New 5-HT6 Receptor Chemotypes

Synthetic derivatives of spiro[pyrrolidinyl-3,3'-oxindole] alkaloids (coerulescine analogues) were investigated as new ligands for aminergic G-protein coupled receptors (GPCRs). The chemical starting point 2'-phenylspiro[indoline-3,3'-pyrrolidin]-2-one scaffold was identified by virtu...

Full description

Saved in:
Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2017-12, Vol.22 (12), p.2221
Main Authors: Kelemen, Ádám A, Satala, Grzegorz, Bojarski, Andrzej J, Keserű, György M
Format: Article
Language:English
Subjects:
5-HT6R
Alkaloids
Animals
CHO Cells
coerulescine
Cricetulus
G-protein coupled receptor
HEK293 Cells
Humans
Identification methods
Indoles - chemical synthesis
Indoles - pharmacology
indoline
Ligands
Molecular Docking Simulation
Optimization
oxindole
Oxindoles - chemical synthesis
Oxindoles - pharmacology
Pharmacology
Protein Binding
Pyrrolidine
Pyrrolidines - chemical synthesis
Pyrrolidines - pharmacology
Receptors, Serotonin - metabolism
Serotonin S6 receptors
Spiro Compounds - chemical synthesis
Spiro Compounds - pharmacology
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Synthetic derivatives of spiro[pyrrolidinyl-3,3'-oxindole] alkaloids (coerulescine analogues) were investigated as new ligands for aminergic G-protein coupled receptors (GPCRs). The chemical starting point 2'-phenylspiro[indoline-3,3'-pyrrolidin]-2-one scaffold was identified by virtual fragment screening utilizing ligand- and structure based methods. As a part of the hit-to-lead optimization a structure-activity relationship analysis was performed to explore the differently substituted 2'-phenyl-derivatives, introducing the phenylsulphonyl pharmacophore and examining the corresponding reduced spiro[pyrrolidine-3,3'-indoline] scaffold. The optimization process led to ligands with submicromolar affinities towards the 5-HT₆ receptor that might serve as viable leads for further optimization.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules22122221