Opioids are the primary target to treat severe pain and are also involved in the modulation of mood and emotions. However, the abuse of these compounds is a severe public health problem due to adverse effects such as tolerance and addiction. Therefor, there is still a need for painkillers with lesser side effects. Although complex and not fully understood, evidence suggests that internalization of the mu opioid  receptor (MOR) to the interior of the cell is associated with tolerance. Herkinorin, an analogue of salvinorin A, has partial selectivity and agonistic effect to the MOR over the subtypes kappa and delta opioid receptors (KOR, DOR). Herkinorin lacks the positively charged nitrogen atom, found in all previously known MOR ligands, does not promote recruitment of β-arrestin-2 and, unlike morphine, herkinorin does not lead to receptor internalization. In this work, we provide a binding recognition model of herkinorin in the MOR that is in agreement with experimental evidence. Reference molecules, morphine and naloxone, were also analyzed. Lastly, insights on MOR signaling pathways and sodium allosteric modulation are presented.

Allosteric modulation model of the mu opioid receptor by herkinorin via docking, molecular dynamics simulations and alchemical free energy calculations

254th National Meeting (2017)

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