A Ligand-Triggered Receptor Conformation Enables the Design of Selective Agonists for the Dopamine 3 Receptor (D₃R)...

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• G protein-coupled receptors (GPCRs) are major drug targets, but subtype selectivity remains difficult, especially for dopamine D2R and D3R.
• Dopamine receptors are crucial for motor control, cognition, and treating conditions like Parkinson's disease and schizophrenia.

Purpose of the Study:

• To design and synthesize highly selective dopamine D3R agonists.
• To explore a novel ligand-induced TM1 binding site for drug development.

Main Methods:

• Rational bitopic drug design targeting a ligand-induced TM1 conformation in D3R.
• Synthesis and characterization of novel D3R agonists.
• Subtype selectivity assays to determine binding affinities and efficacies.

Main Results:

• Discovery of a unique ligand-induced TM1 ordering in D3R, creating a new selectivity site.
• Development of D3R partial agonists (AB12-82 and AB13-73A) with >575,000-fold selectivity and picomolar potency.
• Identification of D3R full agonists (AB13-08 and AB13-46A) with subnanomolar potency and >2,800-fold selectivity.
• Achieved >100,000-fold selectivity, significantly exceeding existing ligands.

Conclusions:

• Ligand-induced TM1 reorganizations offer a promising strategy for developing subtype-selective GPCR ligands.
• The novel D3R agonists provide a powerful pharmacological toolbox for neuroscience research.
• This work opens new avenues for designing improved neurotherapeutics targeting D3R.