Molecular modeling of salsolinol, a full G i protein agonist of the μ‐opioid receptor, within the receptor binding site

( R / S )‐Salsolinol is a full agonist of the μ‐opioid receptor (μ OR ) G i protein pathway via its ( S )‐enantiomer and is functionally selective as it does not promote β‐arrestin recruitment. Compared to ( S )‐salsolinol, the ( R )‐enantiomer is a less potent agonist of the G i protein pathway. We have now studied the interactions of the salsolinol enantiomers docked in the binding pocket of the μ OR to determine the molecular interactions that promote enantiomeric specificity and functional selectivity of ( R / S )‐salsolinol. Molecular dynamics simulations showed that ( S )‐salsolinol interacted with 8 of the 11 residues of the μ OR binding site, enough to stabilize the molecule. ( R )‐Salsolinol showed higher mobility with fewer prevalent bonds. Hence, the methyl group bound to the ( S )‐stereogenic center promoted more favorable interactions in the μ OR binding site than in the ( R )‐orientation. Because ( S )‐salsolinol is a small molecule (179.2 Da), it did not interact with residues implicated in the binding of larger morphinan agonists that are located toward the extracellular portion of the binding pocket: W318 7.35 , I322 7.39 , and Y326 7.43 . Our results suggest that contact with residues which ( S )‐salsolinol interacts with are enough to elicit G i protein activation, and possibly define a minimum set required by μ OR ligands to promote activation of the G i protein pathway.