Racemic Salsolinol and its Enantiomers Act as Agonists of the μ-Opioid Receptor by Activating the Gi Protein-Adenylate Cyclase Pathway.
Background: Several studies have shown that the ethanol-derived metabolite salsolinol (SAL) can activate the mesolimbic system, suggesting that SAL is the active molecule mediating the rewarding effects of ethanol.In vitroandin vivostudies suggest that SAL exerts its action on neuron excitability through a mechanism involving opioid neurotransmission. However, there is no direct pharmacologic evidence showing that SAL activates opioid receptors.Methods: The ability of racemic (R/S)-SAL, and its stereoisomers (R)-SAL and (S)-SAL, to activate the μ-opioid receptor was tested in cell-based (light-emitting) receptor assays. To further characterizing the interaction of SAL stereoisomers with the μ-opioid receptor, a molecular docking study was performed using the crystal structure of the μ-opioid receptor.Results: This study shows that SAL activates the μ-opioid receptor by the classical G protein-adenylate cyclase pathway with an half-maximal effective concentration (EC50) of 2 × 10-5M. The agonist action of SAL was fully blocked by the μ-opioid antagonist naltrexone. The EC50for the purified stereoisomers (R)-SAL and (S)-SAL were 6 × 10-4M and 9 × 10-6M respectively. It was found that the action of racemic SAL on the μ-opioid receptor did not promote the recruitment of β-arrestin. Molecular docking studies showed that the interaction of (R)- and (S)-SAL with the μ-opioid receptor is similar to that predicted for the agonist morphine.Conclusions: It is shown that (R)-SAL and (S)-SAL are agonists of the μ-opioid receptor. (S)-SAL is a more potent agonist than the (R)-SAL stereoisomer.In silicoanalysis predicts a morphine-like interaction between (R)- and (S)-SAL with the μ-opioid receptor. These results suggest that an opioid action of SAL or its enantiomers is involved in the rewarding effects of ethanol.
Program of Molecular and Clinical Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, University of ChileSantiago, Chile; Department of Environmental Health Sciences, Yale School of Public HealthNew Haven, CT, USA.
Pablo
P
Berríos-Cárcamo
Program of Molecular and Clinical Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile Santiago, Chile.
María E
ME
Quintanilla
Program of Molecular and Clinical Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile Santiago, Chile.
Mario
M
Herrera-Marschitz
Department of Environmental Health Sciences, Yale School of Public Health New Haven, CT, USA.
Vasilis
V
Vasiliou
Department of Analytical and Inorganic Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile Santiago, Chile.
Gerald
G
Zapata-Torres
Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile Santiago, Chile.
Mario
M
Rivera-Meza
molecular docking; naltrexone; salsolinol; β-arrestin; μ-opioid receptor