Decahydroquinoline alkaloids: Noncompetitive blockers for nicotinic acetylcholine receptor-channels in pheochromocytoma cells andTorpedo electroplax

Abstract

In pheochromocytoma PC12 cells, (+)-cis-decahydroquinoline 195A (5-methyl-2-propyl-cis-decahydroquinoline) and (+)-perhydro-cis-decahydroquinoline 219A (2,5-dipropyl-cis-decahydroquinoline) inhibit carbamylcholine-elicited sodium flux with IC50 values of 1.0 and 1.5 microM, respectively. Both of these decahydroquinolines appear to enhance desensitization, although apparent lack of complete removal of (+)-perhydro-cis-219A by washing complicates interpretation of the effects of that agent. A series of cis- and trans-decahydroquinolines with substituents in the 2- and 5-position also exhibit structure-dependent inhibition of carbamylcholine-elicited sodium flux in PC12 cells and all of the decahydroquinolines inhibit binding of the noncompetitive blocking agent [3H]perhydrohistrionicotoxin to muscle-type nicotinic acetylcholine receptor-channels in membranes from Torpedo electroplax. The Ki values in electroplax membranes range from 1.4 to 7.9 microM, making these alkaloids comparable in potencies to the histrionicotoxins. Potencies are increased 2- to 3-fold in the presence of an agonist, carbamylcholine. The profile of activities are similar in PC12 cells and electroplax membranes. The cis- and trans-decahydroquinolines represent another class of noncompetitive blockers for acetylcholine receptor-channels with similar activity for both muscle-type and ganglionic type nicotinic receptors.

Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis

“…Although lobinaline lacks a pyridyl functional group, the aromatic character of its phenyl substituents in the vicinity of the 1,2-dehydropiperidine functional group may suffice to create a physiochemical environment adequate to engender similar interactions with nicAchRs. The agonist activity lobinaline displays at nicAchRs is of note, given other decahydroquinolines studied to date antagonize nicAchRs, possibly due to the lack of a tetrahydropiperidyl substituent in those previously investigated [100, 101]. Lobinaline has 5 chiral centers, whose stereogenic configuration in the natural molecule from the plant is unknown.…”

Development of a Second Generation Palladium-Catalyzed Cycloalkenylation and its Application to Bioactive Natural Product Synthesis

“…Together, the results showed that compounds 23 afforded better yields (entries 1-5) as compared to compounds 26 (entries 6-10). [17]. Since then, cis-195A (29) has been an attractive and challenging target in organic synthesis because of its intriguing pharmacological properties and unique structure [18].…”

Seasonal Changes in Diet and Toxicity in the Climbing Mantella Frog (Mantella Laevigata)

“…Yet extensive sampling of both lineages over several decades has revealed the presence of hundreds of similar alkaloid toxins [5]. Examples include histrionicotoxins, pumiliotoxins, and decahydroquinolines that target sodium and nicotinic acetylcholine channels in the nervous system [19][20][21]. There is some evidence that toxin autoresistance has also convergently evolved in dendrobatids and mantellids, where similar mutations in the sodium channel pore have been documented and hypothesized to confer alkaloid resistance in these two frog families [22].…”