Vol. 302, Issue 3, 853-860, September 2002

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

Alan P. Robertson, Cheryl L. Clark, Teresa A. Burns, David P. Thompson, Timothy G. Geary, Sasa M. Trailovic and Richard J. Martin

Department of Biomedical Sciences, Iowa State University, Ames, Iowa (A.P.R., C.L.C., T.A.B., S.M.T., R.J.M.); and Pharmacia Animal Health, Kalamazoo, Michigan (D.P.T., T.G.G.)

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 in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.