Paraherquamide and 2-Deoxy-paraherquamide Distinguish Cholinergic Receptor Subtypes in Ascaris Muscle

Abstract

Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK_B values of the antagonists. The analysis was tested using Clark plots. The pK_B values for paraherquamide were: nicotine, 5.86 ± 0.14; levamisole, 6.61 ± 0.19; pyrantel, 6.50 ± 0.11; and bephenium, 6.75 ± 0.15. The pK_B of nicotine was significantly different from the pK_B values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK_B values for 2-deoxy-paraherquamide were: levamisole, 5.31 ± 0.13; pyrantel, 5.63 ± 0.10; and bephenium, 6.07 ± 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK_B values of levamisole and pyrantel were significantly different from the pK_B of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor inAscaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.