Investigation on MOR receptor activation by atypical mechanisms

The recent discovery of some agonists at opioid receptor lacking the protonatable amino group [1], leads to the re-discussion of the importance of ionic interactions in stabilizing the ligand-receptor complex and in activating signal transduction. Recently, we have synthesized cyclic analogues of endomorphin-1 (EM-1), containing different Xaa5 bridges between Tyr1 and Phe4. These lipophilic, cyclic EM-1 analogues displayed good affinities for MORs, allowing to hypothesize that they could interact with the receptor by a peculiar, alternative fashion, which has been investigated by Molecular Docking. The docking results gave a detailed description of ligand binding interactions and their electronic properties. The comparison with the agonist JOM-6 binding mode [50,51] indicated that the cyclic EM-1 analogues have an alternative interaction mechanism, still maintaining the ability to activate the receptor.