Related Experiment Video
Updated: Jun 8, 2026

Characterizing Modulators of Protease-Activated Receptors with a Calcium Mobilization Assay Using a Plate Reader
Published on: May 24, 2024
Bioisosteric replacement leading to biologically active [2.2]paracyclophanes with altered binding profiles for
Marika Skultety1, Harald Hübner, Stefan Löber
1Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
Abstract:
Exploring the chemical diversity space of GPCR ligands, we recently discovered [2.2]paracyclophanes as valuable atypical bioisosteres for secondary affinity and selectivity generating moieties. To find out if such an exchange also works for structural moieties that simulate the endogenous neurotransmitter, π1 or π2 or both systems π1 and π2 of three representative privileged structures of types 1, 2, and 3 were replaced by a [2.2]paracyclophane unit. Contributions of the respective functionalities to the binding affinities of a panel of relevant monoaminergic GPCRs were systematically examined. The study led to the paracyclophanylpiperazine 3a displaying excellent D(3) affinity (K(i) = 1.6 nM) and a strongly attenuated binding to D(4), 5-HT(1) and α(1). Whereas functional experiments showed neutral D(3) antagonist properties, mutagenesis studies indicated a binding mode that is similar to its lead compounds of type 3.
More Related Videos
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
09:21BRET-based G Protein Biosensors for Measuring G Protein-Coupled Receptor Activity in Live Cells
Published on: November 7, 2025
Related Concept Videos
The Two-State Receptor Model
The binding affinity of a drug determines its interaction with one...
GPCRs Regulate Adenylyl Cylase Activity
Two...
Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
GPCR Desensitization
Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
G Protein-coupled Receptors
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...