14.10.2020 | Webinar: Pharmacological Characterization of Natural Tobacco Alkaloids in the Presence of Positive Allosteric Modulators Against Humana4b2 and a7 Nicotinic Acetylcholine Receptors
Date: October 14. 2020
Dr. Omar Alijevic (Philip Morris International)
This is an on-demand webinar from Nan]i[on and Friends 2020.
The pharmacological profile of tobacco alkaloids is essential for understanding their physiological effects. Nicotinic acetylcholine receptors (nAChRs) are an important target of tobacco alkaloids with primarily agonistic effects reported for α4β2 nAChRs, but with minimal evidence of α7 activity. In this study, we used a membrane potential assay and automated patch-clamp electrophysiological approaches to functionally characterize distinct groups of tobacco alkaloids in the presence of a subunit-specific positive allosteric modulator (PAM) of human α4β2 and α7 nAChRs. We screened a total of 71 tobacco alkaloids, of which 16 were active against α4β2 and 11 against α7 nAChRs.
The most abundant alkaloids in tobacco leaves—namely nicotine, nornicotine, anabasine, (S)-anatabine, and (R)-anatabine—exhibited potencies (EC50alkaloid+PAM) of 0.02-20 μM against α4β2 and 0.2-10 μM against α7 nAChRs. In the presence of the PAM, nicotine and anabasine, respectively, were found to be the most potent α4β2 and α7 nAChRs agonists. Relative to (S)-anatabine, (R)-anatabine was 5-fold more potent against α4β2; the relationship was found to be inverse in case of α7 nAChRs. In addition, 13 alkaloids demonstrated agonistic effects only in the presence of the PAM and were, therefore, considered to be silent agonists. In conclusion, the data revealed 17 naturally occurring tobacco alkaloids that exhibited a dramatic increase in potency against human α4β2 and α7 nAChRs in the presence of PAMs (relative to that in the absence of the PAM). Our study recognized a subunit-specific enantiomer preference of anatabine and identified several alkaloids with silent agonist properties for human α4β2 and α7 nAChRs.