Substituted Purines as High-Affinity Histamine H₃ Receptor Ligands

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Chemistry

Background:

• Histamine H3 receptor (H3R) ligands are pursued for therapeutic applications.
• Previous work identified pyrrolo[2,3-d]pyrimidine scaffolds for H3R antagonism.

Purpose of the Study:

• To synthesize and evaluate novel purine derivatives as H3R ligands.
• To investigate the structure-activity relationships and binding modes of these new compounds.

Main Methods:

• Synthesis of eight purine derivatives.
• In vitro H3R affinity screening (Ki values).
• In silico studies including docking, molecular dynamics, and ADME predictions.

Main Results:

• Two compounds, 3d and 3h, exhibited high affinity for H3R (Ki = 2.91 nM and 5.51 nM, respectively).
• These compounds demonstrated greater potency than pitolisant (Ki = 6.09 nM) and low in vitro toxicity (IC50 > 30 µM).
• Molecular modeling revealed key interactions, including hydrogen bonding between Tyr374 and the purine N-7, contributing to enhanced affinity.

Conclusions:

• The novel purine derivatives are potent and selective H3R ligands.
• The purine scaffold is a promising core for developing new H3R-targeting drugs.
• In silico ADME predictions suggest favorable pharmacokinetic properties for CNS penetration.