Adenine nucleotides as potent and selective GPR17 modulators

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• G protein-coupled receptor GPR17 is vital for oligodendrocyte maturation and myelination in the brain.
• Dysregulation of GPR17 is linked to neurodegenerative conditions such as multiple sclerosis and brain ischemia.
• Targeting GPR17 presents a promising therapeutic avenue for central nervous system (CNS) disorders.

Purpose of the Study:

• To synthesize and characterize novel adenine nucleotide derivatives as modulators of GPR17.
• To evaluate the potency, efficacy, and selectivity of these novel compounds against GPR17 and related purinergic receptors.

Main Methods:

• Chemical synthesis of modified adenine nucleotides, including triphosphate and bisphosphate derivatives with substitutions on the adenine core.
• Functional assays using HEK293 L9-2 cells transiently transfected with human GPR17.
• Selectivity profiling against human purinergic P2Y12, P2Y13, and P2Y14 receptors.

Main Results:

• The synthesized novel compounds demonstrated high potency (nanomolar to picomolar) and varied efficacy profiles at GPR17.
• The developed molecules exhibited selectivity for GPR17 over other tested purinergic receptors (P2Y12, P2Y13, P2Y14).

Conclusions:

• Novel adenine nucleotide derivatives effectively modulate GPR17 activity with high potency and selectivity.
• These findings support the development of GPR17-targeting therapeutics for CNS disorders involving myelin defects and neurodegeneration.