Decahydroquinoline alkaloids: noncompetitive blockers for nicotinic acetylcholine receptor-channels in pheochromocytoma cells and Torpedo electroplax.
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.
Daly
J W
JW
Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
Nishizawa
Y
Y
Padgett
W L
WL
Tokuyama
T
T
McCloskey
P J
PJ
Waykole
L
L
Schultz
A G
AG
Aronstam
R S
RS
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D004557:Electric Organ / Q000187:drug effects*; D015394:Molecular Structure; D018733:Nicotinic Antagonists; D016716:PC12 Cells; D011804:Quinolines / Q000494:pharmacology*; D011869:Radioligand Assay; D014101:Torpedo
D000470:Alkaloids; D018733:Nicotinic Antagonists; D011804:Quinolines; C011093:pumiliotoxin C; C074597:2,5-dipropyldecahydroquinoline