P2Y₁₄ Receptor Antagonists: Piperidine Bioisosteres and Mutagenesis-Supported Molecular Modeling.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Neuroscience

Background:

• The human P2Y14 receptor (hP2Y14R) is a potential therapeutic target for inflammation and pain.
• Existing zwitterionic antagonists for hP2Y14R exhibit poor bioavailability.
• Structure-activity relationship (SAR) studies are crucial for developing effective hP2Y14R antagonists.

Purpose of the Study:

• To optimize naphthalene-based hP2Y14R antagonists by modifying the piperidine moiety with heteroaromatics.
• To investigate the binding site interactions and mechanism of action of hP2Y14R antagonists.
• To evaluate the in vivo efficacy and safety profile of novel hP2Y14R antagonists.

Main Methods:

• Synthesis and SAR analysis of novel naphthalene-based hP2Y14R antagonists.
• Site-directed mutagenesis and molecular dynamics simulations to determine antagonist binding modes.
• In vivo assessment of oral efficacy in a mouse model of mechanoallodynia.
• Evaluation of hypothermic effects induced by a selective P2Y14R agonist.

Main Results:

• Novel heteroaromatic substitutions, specifically C-linked 1,2,3-triazol-4-yl (10) and pyrazol-3-yl (11), yielded potent hP2Y14R antagonists with nanomolar IC50 values.
• Molecular dynamics identified a key interaction between the antagonist's carboxylate and R253, suggesting a minimally orthosteric binding mechanism.
• Compound 11 demonstrated significant oral efficacy in reversing mechanoallodynia in mice.
• Selective P2Y14R agonist MRS2905 induced hypothermia, while antagonists 1 and 11 did not, indicating a favorable safety profile.

Conclusions:

• The study successfully refined the hP2Y14R antagonist binding model.
• New drug-like scaffolds with enhanced solubility and CNS penetration potential were introduced.
• These findings provide a foundation for future optimization and virtual screening efforts targeting P2Y14R for therapeutic applications.