Drimane sesquiterpenoids purified from Drimys winteri inhibit the human α4β2 nicotinic acetylcholine receptor by noncompetitive mechanisms

ABSTRACT Background and Purpose The aim of this study is to evaluate the pharmacological activity of four natural drimane sesquiterpenoids on human (h) α4β2 nicotinic acetylcholine receptors (AChRs), the most abundant receptor subtype in the brain. Experimental Approach The drimane sesquiterpenoids, drimenin, cinnamolide, dendocarbin A, and polygodial, were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds was subsequently determined in vitro on hα4β2 AChRs by Ca2+ influx. To determine the structural components underlying the differences in inhibitory potency, structure-activity relationship, molecular docking and molecular dynamics experiments were performed on the hα4β2 AChR model. Key Results Drimane sesquiterpenoids, except dendocarbin A, inhibit hα4β2 AChRs with the following potency rank order: drimenin ~ cinnamolide > polygodial. The Ca2+ influx and structural results supported the view that these compounds inhibit hα4β2 AChRs in a noncompetitive manner, by interacting mainly with a non-luminal site located at the transmembrane region of the β2 subunit. Conclusion and Implications Drimenin sesquiterpenoids are novel hα4β2 AChR inhibitors. Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR. Drimenin derivatives might be developed as novel therapeutic approaches for the treatment of drug addictions, depression, and anxiety