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 mu M, while spiropyrrolizidine oxime 222 had an IC50 value of 2.6 mu M 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 mu M, 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 [H-3]nicotine to alpha(4) beta(2) nicotinic receptors was not inhibited significantly by 10 mu M concentrations of the spiropyrrolizidine oxime 236, or by nitropolyzonamine, as expected for a noncompetitive blocker. Both compounds at 10 mu M had marginal effects on a variety of central receptors, but did inhibit binding of [H-3] 1,3-di(2-tolyl)guanidine to sigma receptors in mouse brain membranes with IC50 values of about 0.5 mu M. The spiropyrrolizidine oxime 236 at 10 mu M 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.