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Open AccessArticle

Investigation of the Possible Pharmacologically Active Forms of the Nicotinic Acetylcholine Receptor Agonist Anabaseine

1
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
2
Department of Chemistry, University of Florida, Gainesville, FL 32610, USA
3
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610; USA
4
USDA-ARS Poisonous Plant Research Laboratory, Logan, UT 84341, USA
5
Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
Denotes first authors.
Mar. Drugs 2019, 17(11), 614; https://doi.org/10.3390/md17110614
Received: 23 August 2019 / Revised: 24 October 2019 / Accepted: 24 October 2019 / Published: 29 October 2019
(This article belongs to the Special Issue Marine Toxins Affecting Cholinergic System)
Three major forms of the nicotinic agonist toxin anabaseine (cyclic iminium, cyclic imine and the monocationic open-chain ammonium-ketone) co-exist in almost equal concentrations at physiological pH. We asked the question: Which of these forms is pharmacologically active? First, we investigated the pH dependence of anabaseine inhibition of [3H]-methylcarbamylcholine binding at rat brain α4β2 nicotinic acetylcholine receptors (nAChRs). These experiments indicated that one or both monocationic forms interact with the orthosteric binding site for ACh. However, since they occur at equal concentrations near physiological pH, we employed another approach, preparing a stable analog of each form and examining its agonist activities and binding affinities at several vertebrate brain and neuromuscular nAChRs. Only 2-(3-pyridyl)-1,4,5,6-tetrahydropyrimidine monohydrogen chloride (PTHP), the cyclic iminium analog, displayed nAChR potencies and binding affinities similar to anabaseine. The cyclic imine analog 2,3′-bipyridyl and the open-chain ammonium-ketone analog 5-methylamino-1-(3-pyridyl)-1-pentanone (MAPP), displayed ≤1% of the activity predicted if the one form was solely active. The lower potency of weakly basic 2,3′-bipyridyl can be explained by the presence of a small concentration of its monocationic form. Since the open chain ammonium-ketone monocationic form of anabaseine has some structural similarity to the neurotransmitter GABA, we also tested the ability of anabaseine and its 1,2-dehydropyrrolidinyl analog myosmine to activate a mammalian GABAA receptor, but no activity was detected. We conclude that the monocationic cyclic iminium is the form which avidly binds and activates vertebrate nAChRs. View Full-Text
Keywords: acetylcholine; alkaloid; anabaseine; bipyridyl; cholinergic; nicotine; nicotinic acetylcholine receptor; ring-chain tautomerism; toxin acetylcholine; alkaloid; anabaseine; bipyridyl; cholinergic; nicotine; nicotinic acetylcholine receptor; ring-chain tautomerism; toxin
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MDPI and ACS Style

Andrud, K.; Xing, H.; Gabrielsen, B.; Bloom, L.; Mahnir, V.; Lee, S.; Green, B.T.; Lindstrom, J.; Kem, W. Investigation of the Possible Pharmacologically Active Forms of the Nicotinic Acetylcholine Receptor Agonist Anabaseine. Mar. Drugs 2019, 17, 614.

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