Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes

Abstract

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 were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) ≫ dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally ( n > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.

Insecticidal and Antifeedant Activities of Malagasy Medicinal Plant (Cinnamosma sp.) Extracts and Drimane-Type Sesquiterpenes against Aedes aegypti Mosquitoes

“…Thus, our results suggest that the mechanism of 4 ’s antifeedant activity is distinct from 1 , 9 , and 10 , and remains to be elucidated. In humans, 4 has been shown to interact with acetylcholine receptors [73], and possess cytotoxic activity [44]. Whether 4 can interact with similar receptors or have similar activities in insects to induce antifeedant or repellent behaviors remains to be determined.…”

Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against Candida Yeast by Inhibition of Lanosterol 14-Alpha Demethylase

“…A plausible pathway for the formation of C2 involves allylic oxidation with double bond migration and elimination of water, which is facilitated by the well-known slightly acidic character of the PCC reagent [33]. Compound C3, also called drimenin, an annellated β-alkylidene-γ-lactone, was previously isolated from Drimys winteri [14], but has also been synthesized from racemic albicanol via lipase catalyzed kinetic resolution in a multiple step approach [34]. Analytical data obtained by us match those previously reported.…”

“…The purification of isodrimeninol (C1) was done by preparative column chromatography from a sub-fraction of Drimys winteri, previously extracted from barks of the tree macerated with ethyl acetate (EtOAc), which was kept at −80 • C with the code F5 [14]. In this work, the fraction F5 was further purified by Silica gel column chromatography.…”

“…The phytochemical richness and pharmacological potential of Drimys winteri is remarkable. For example, bioactive sesquiterpene lactones such as cinnamolide and drimenin have been isolated from this source showing potent inhibitory activity against the human α4β2 nicotinic acetylcholine receptors that are involved in drug addiction [14]. Also, alcohols such as drimendiol have shown antibacterial quorum sensing activity [15,16] and they have been used as a scaffold for the hemisynthesis of nitrogenated derivatives with antifungal activity against Candida albicans [17].…”

Phytochemistry and biological properties of Drimys winteriJR et G. Forster var chilensis(DC) A.

“…Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally (nH > 1). Drimenin could be a start point for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR (Arias et al, 2018).…”