Spiropyrrolizidines: a new class of blockers of nicotinic receptors.
The spiropyrrolizidine oximes 236 and 222 and a related spiropyrrolizidine alkaloid, nitropolyzonamine, block nicotinic receptor channels in rat pheochromocytoma PC12 cells and in human medulloblastoma TE671 cells. In PC12 cells with an alpha 3 beta 4(5)-nicotinic receptor, both the spiropyrrolizidine oxime 236 and nitropolyzonamine had IC50 values of about 1.5 microM, while spiropyrrolizidine oxime 222 had an IC50 value of 2.6 microM versus carbamylcholine-elicited sodium-22 influx. In TE671 cells with an alpha 1 beta 1 gamma delta nicotinic receptor, the spiropyrrolizidine oximes 236, 222, and nitropolyzonamine had IC50 values of 9.5, 14, and 67 microM, respectively. The inhibitions by the spiropyrrolizidine oxime 236 and nitropolyzonamine appeared to be noncompetitive in nature in both cell lines. In rat cerebral cortical membranes, binding of [3H]nicotine to alpha 4 beta 2 nicotinic receptors was not inhibited significantly by 10 microM concentrations of the spiropyrrolizidine oxime 236, or by nitropolyzonamine, as expected for a noncompetitive blocker. Both compounds at 10 microM had marginal effects on a variety of central receptors, but did inhibit binding of [3H]1,3-di(2-tolyl) guanidine to sigma receptors in mouse brain membranes with IC50 values of about 0.5 microM. The spiropyrrolizidine oxime 236 at 10 microM had no effect on batrachotoxin-elicited sodium influx in guinea pig cerebral cortical synaptoneurosomes or on ATP-elicited calcium influx in PC12 cells. Such spiropyrrolizidines represent a new structural class of blockers of nicotinic receptor channels with selectivity for ganglionic-type receptors.
Badio
B
B
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Shi
D
D
Shin
Y
Y
Hutchinson
K D
KD
Padgett
W L
WL
Daly
J W
JW
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D018733:Nicotinic Antagonists / Q000145:classification / Q000378:metabolism*; D016716:PC12 Cells / Q000187:drug effects; D011763:Pyrrolizidine Alkaloids / Q000145:classification / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats
D018733:Nicotinic Antagonists; D011763:Pyrrolizidine Alkaloids; C101414:spiropyrrolizidine oxime 222; C101413:spiropyrrolizidine oxime 236