The Areca nut is well known in southeastern Asia as the source of muscarinic active alkaloids that constitute a popular addictive drug known as the betel quid, in which limed extracts of the nut are rolled in betel vine leaves and in some cases, include tobacco. Of the four known alkaloids in Areca, arecoline is the most active muscarinic agonist while guvacoline is less potent. Arecaidine is an M2 selective agonist. Muscarinic activity has not been reported for guvacine, a GABA transport inhibitor. Two electrode voltage clamp electrophysiology experiments in Xenopus oocytes expressing muscarinic or nicotinic receptors have revealed that in addition to muscarinic activity, arecoline displays weak nicotinic partial agonism with a selectivity profile favoring α4β2 and α6β2β3α4β2 subtypes considered as targets for therapeutics aimed at nicotine addiction, while avoiding α7, α3β4, and muscle-type nAChR. This is in contradistinction to the known therapeutics cytisine and varenicline which although capable of partial agonism at α4β2 and α6β2β3α4β2 receptors, are strong agonists of the α7 receptor, and show significant activity at ganglionic α3β4 receptors. The arecoline analog isoarecolone shows an even more pronounced selectivity for α4β2 and α6β2β3α4β2 receptors compared to arecoline. It is noteworthy that whereas arecoline shows significant muscarinic activity, primarily at M1 mAChR, isoarecolone has nearly abolished activity at M1 and significantly reduced mAChR activity in assays against co-expressed M1, M2, and M3 receptors. Isoarecolone thus represents an interesting template for the development of new agents targeting α4β2 and α6β2β3α4β2 receptors. Interestingly we have found that Areca extracts also demonstrate an inhibitory component acting at nicotinic receptors. Fractionation based on size revealed that while both mAChR and nAChR activities resided in the low molecular weight fraction &lt; 1 kDa, the inhibitory component was large with an estimated size &gt; 10 kDa. These results will be discussed in the context of development of new therapeutics aimed at smoking cessation.

Selective nicotinic acetylcholine receptor activities from the areca nut

253rd National Meeting (2017)

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