Activity against the coccidial pathogen Eimeria tenella in chickens has been discovered among a2 adrenergic agonists. The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine was active in feed at 7.5 ppm, a concentration similar to the use levels of potent commercial agents, e.g., maduramicin. Additional a2 agonists were also found to have anticoccidial activity, for example, the catecholamine nordefrin, which is chemically unrelated to clonidine. However, al agonists and a antagonists were inactive. These observations imply that anticoccidial effects reflect involvement of a receptor with the characteristics of the vertebrate a2 adrenoceptor. a2 agonists that permeate the blood-brain barrier (like clonidine) inhibit feed intake at efficacious levels, whereas those that are restricted to the peripheral compartment (such as catecholamines) do not inhibit feed intake as much. Hence, anticoccidial efficacy may be a peripheral adrenergic effect whereas depression of feed intake is likely centrally mediated.Coccidiosis, an intestinal disease of great economic importance in the poultry industry, is caused by intracellular protozoan parasites of the genus Eimeria. Although more than 20 different anticoccidial agents have been commercialized, the current drugs of choice belong to a single class: the polyether ionophores. Because of the ever-present threat that coccidia will develop resistance to these agents, there is a continuing need to discover new classes of anticoccidial agents.In the course of evaluating compounds from our files, 7-bromo-N-(2-imidazolidinylidene)-lH-indazol-6-amine (compound I) proved to be active against Eimeria tenella infections in chickens; however, it led to low weight gains. Compound I was prepared originally as a clonidine analog. Clonidine produces a variety of effects, owing to its a2 adrenergic agonist activities, and has found clinical use as an antihypertensive agent (7). Compound I also shows a2 agonist properties (3). We therefore explored the possibility that the observed anticoccidial activity was dependent upon stimulation of a2 adrenoceptors. If this were the case, it would follow that other a2 agonists, those structurally unrelated to clonidine, would show this effect. Conversely, a1 adrenergic agonists and a antagonists should be inactive. To test this hypothesis, we evaluated the anticoccidial activities of a variety of a adrenergic agents.We discovered that (i) among a adrenergic agents, anticoccidial activity is associated only with a2 agonists; (ii) a2 agonists other than clonidine analogs are also effective; and (iii) a2 agonists that cannot cross the blood-brain barrier, such as catecholamines, are effective and at the same time not as weight suppressive.MATERIALS AND METHODS General. Melting points are uncorrected. Yields were not maximized. All compounds had 'H nuclear magnetic resonance spectra that were consistent with their assigned structures. The following agents were either purchased from * Corresponding author. 7-Bromo-lH-indazol-6-amine. A solu...
The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine exhibits potent activity against Eimeria tenella infections in chickens. Disease control was abrogated by a selective alpha 2 antagonist, which is consistent with the dependence of such activity upon binding to receptors with characteristics of the vertebrate alpha 2 adrenoceptor. Lack of significant activity against the parasite in tissue culture and our inability to detect significant binding of alpha 2 adrenergic ligands to E. tenella imply that the anticoccidial action may be an indirect effect mediated by the host. Efficacy varied, depending upon the Eimeria species, being greatest for the cecal species E. tenella and less for the intestinal species. The effects described differ substantially from previous accounts of adrenergic actions on parasitic protozoa. The evidence suggests that we have observed a new mechanism of action for antiparasitic drugs.
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