A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

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.

Pyridine alkaloids with activity in the central nervous system

“…4 ) is the second most abundant alkaloid (~4%) present in Nicotiana species. 36 , 48 This alkaloid was first isolated from the leaves of N. tabacum by Spath and Kesztler in 1937, who also established the chemical structure through total synthesis. 49 Anatabine is a pyridine-dihydropyridine structurally related to anabasine.…”

“… 49 Anatabine is a pyridine-dihydropyridine structurally related to anabasine. 48 Subsequent studies reported that anatabine exists as an 85:15 scalemic mixture of (−)- and (+)-enantiomers in Nicotiana species. 50 …”

“…The binding affinities (K i ) of (−)- and (+)-anatabine were evaluated at rat α4β2-nAChR by displacement of [ 3 H]-cytisine radioligand binding using anabasine and nicotine as comparisons. 48 Kem and co-workers demonstrated that (+)-anatabine (K i = 119 nM) exhibited a higher binding affinity than (−)-anatabine (K i = 249 nM), ~8- and 4-fold more potent than anabasine (K i = 910 nM) respectively; 48 the nicotine K i value was found to be ~2 nM. 48 In the same study, the agonist potency (EC 50 ) and ACh stimulation efficacies (I max ) of both anatabine enantiomers at human α4β2- and α7-nAChRs were also examined.…”

“… 48 Kem and co-workers demonstrated that (+)-anatabine (K i = 119 nM) exhibited a higher binding affinity than (−)-anatabine (K i = 249 nM), ~8- and 4-fold more potent than anabasine (K i = 910 nM) respectively; 48 the nicotine K i value was found to be ~2 nM. 48 In the same study, the agonist potency (EC 50 ) and ACh stimulation efficacies (I max ) of both anatabine enantiomers at human α4β2- and α7-nAChRs were also examined. 48 At the α4β2-subtype receptor, (−)-anatabine (EC 50 = 2.65 µM; I max = 43.2%) was ~2-fold more efficacious than (+)-anatabine (EC 50 = 0.74 µM, I max = 25.0%); much higher efficacies were observed at the α7-receptors for both (−)-anatabine (EC 50 = 69.7 µM; I max = 113%) and (+)-anatabine (EC 50 = 51.8 µM; I max = 105%).…”

“… 48 In the same study, the agonist potency (EC 50 ) and ACh stimulation efficacies (I max ) of both anatabine enantiomers at human α4β2- and α7-nAChRs were also examined. 48 At the α4β2-subtype receptor, (−)-anatabine (EC 50 = 2.65 µM; I max = 43.2%) was ~2-fold more efficacious than (+)-anatabine (EC 50 = 0.74 µM, I max = 25.0%); much higher efficacies were observed at the α7-receptors for both (−)-anatabine (EC 50 = 69.7 µM; I max = 113%) and (+)-anatabine (EC 50 = 51.8 µM; I max = 105%). 48 These findings suggest that anatabine is a selective and potent ligand at α7-nAChRs.…”