Three pharmacological subtypes of
cholinergic receptors have been distinguished in Ascaris suum using a muscle contraction assay and classical pharmacological techniques. The receptor subtypes are: a B-subtype (sensitive to bephenium); an L-subtype (sensitive to
levamisole and
pyrantel); and an N-subtype (sensitive to
nicotine and
methyridine).
Oxantel is a
cholinergic anthelmintic that was first introduced for the treatment of whipworm,
Trichuris, infections in children. Here, we compare the subtype selectivity of
oxantel with thenium and other
cholinergic anthelmintics. We used the A. suum assay to derive pA(2) values for the agonists:
oxantel, thenium, bephenium,
levamisole,
pyrantel,
nicotine and
methyridine with the antagonists:
paraherquamide, 2-desoxyparaherquamide and
methyllycaconitine. pA(2) values, rather than pK(B) values, were determined for all agonists when it was found that Schild slopes for some agonists were significantly less than 1.0. The pA(2) of
oxantel was 6.58+/-0.25 for
paraherquamide; 5.39+/-0.28 for 2-desoxyparaherquamide; 7.01+/-0.19 for
methyllycaconitine. Comparison of pA(2) values using cluster analysis showed that
oxantel was grouped with
nicotine and
methyridine, the N-subtype agonists. Thenium had pA(2)s of 7.84+/-0.41 for
paraherquamide; 5.52+/-0.50 for 2-desoxyparaherquamide; 6.33+/-0.19 for
methyllycaconitine. Cluster analysis placed thenium between the L-subtype agonists and the B-subtype agonist. The therapeutic significance of classification of
cholinergic anthelmintics is discussed. Combination of
oxantel and
pyrantel would have therapeutic advantages, covering N- and L-subtypes, and so increasing spectrum of action and reducing the potential for development of resistance. Our results predict that
oxantel may remain effective in some nematode isolates that have become
levamisole- and
pyrantel-resistant.