New Panx-1 Blockers: Synthesis, Biological Evaluation and Molecular Dynamic Studies.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• The channel protein Pannexin-1 (Panx-1) is implicated in various pathologies including epilepsy, stroke, cancer, and neuropathic pain.
• Panx-1's involvement in disease makes it a significant therapeutic target.
• Previous research identified potent indole derivatives as Panx-1 blockers.

Purpose of the Study:

• To explore novel chemical scaffolds, specifically naphthalene and pyrazole derivatives, as potential Panx-1 blockers.
• To synthesize and evaluate compounds incorporating functional groups (sulfonamide, carboxylic acid, sulfonic acid) known to enhance Panx-1 inhibitory activity.
• To investigate the efficacy of these novel compounds in a preclinical model of neuropathic pain.

Main Methods:

• Synthesis of naphthalene and pyrazole derivatives with specific functional groups.
• In vitro assessment of Panx-1 blocking activity for synthesized compounds.
• Evaluation of anti-hypersensitivity effects in a mouse model of oxaliplatin-induced neuropathic pain.
• Molecular dynamics and Principal Component Analysis (PCA) for structure-activity relationship analysis.

Main Results:

• Compounds 4 and 13 emerged as the most potent Panx-1 blockers, exhibiting inhibition of 97% and 93.7% at 50 µM, respectively.
• Both compounds demonstrated significant anti-hypersensitivity effects in the neuropathic pain model, increasing pain thresholds at 1 and 3 nmol doses.
• Molecular dynamics and PCA identified key factors differentiating active from inactive compounds.

Conclusions:

• Naphthalene and pyrazole scaffolds, functionalized with sulfonamide and carboxylic/sulfonic acid groups, represent a viable strategy for developing novel Panx-1 blockers.
• Compounds 4 and 13 show significant therapeutic potential for neuropathic pain and possibly other Panx-1-related disorders.
• Computational analyses provide insights into the molecular mechanisms underlying Panx-1 inhibition, guiding future drug design.