Abstract

(R/S)-Salsolinol is a full agonist of the mu-opioid receptor (mu OR) G(i) protein pathway via its (S)-enantiomer and is functionally selective as it does not promote beta-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 mu 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 mu 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 mu 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 mu OR ligands to promote activation of the G(i) protein pathway.