Abstract
Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.
Highlights
Due to its many effects on the human organism, (S)-nicotine, the most abundant pharmacologically active constituent of the commercial tobacco plant Nicotiana tabacum, is one of the most thoroughly investigated natural products
Much has been learned about the myriad central nervous system nicotinic acetylcholine receptors that are activated by nicotine and similar “nicotinoid” compounds [1,2,3,4,5]
It has been demonstrated that nicotine and some other nicotinic acetylcholine receptors (nAChRs) agonists have pro-cognitive, anxiolytic, analgesic, and anti-inflammatory properties that might be useful in the treatment of certain neurodegenerative, neurodevelopmental, inflammatory, and drug addiction disorders [4,5,6]
Summary
Due to its many effects on the human organism, (S)-nicotine, the most abundant pharmacologically active constituent of the commercial tobacco plant Nicotiana tabacum, is one of the most thoroughly investigated natural products. (1) isoanatabine, which we isolated from a nemertine (nemertean) worm, Amphiporus angulatus, and (2) anatabine, the most abundant minor alkaloid of the commercial tobacco plant (Figure 1). Both compounds are isomers differing only in the position of a single double bond in an otherwise saturated piperidine ring in the “parent” compound anabasine, which is present in wild tobacco [22]. We investigated the effects of anatabine and anatabine, the most abundant minor alkaloid of the commercial tobacco plant (Figure 1) Both isoanatabine on the two major central nervous system (CNS) nAChRs. compounds are isomers differing only in the position of a single double bond in an otherwise saturated. The pharmacological properties of anabasine [23,24] and the related anabaseine [25,26] have been
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