Binding of the Hemopressin Peptide to the Cannabinoid CB1 Receptor: Structural Insights

Hemopressin, a bioactive nonapeptide derived from the alpha 1 chain of hemoglobin, was recently shown to possess selective antagonist activity at the cannabinoid CBI receptor [Heimann, A. S., et al. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 20588-20593]. CB1 receptor antagonists have been extensively studied for their possible therapeutic use in the treatment of obesity, drug abuse, and heroin addiction. In particular, many compounds acting as CB1 receptor antagonists have been synthesized and subjected to experiments as possible anti-obesity drugs, but their therapeutic application is still complicated by important side effects. Using circular dichroism and nuclear magnetic resonance spectroscopy, this work reports the conformational analysis of hemopressin and its truncated, biologically active fragment hemopressin(1-6). The binding modes of both hemopressin and hemopressin(1-6) are investigated by molecular docking calculations. Our conformational data indicate that regular turn structures in the central portion of hemopressin and hemopressin(1-6) are critical for an effective interaction with the receptor. The results of molecular docking calculations, indicating similarities and differences in comparison to the most accepted CB1 pharmacophore model, suggest the possibility of new chemical scaffolds for the design of new CB1 antagonist lead compounds.