UNIQUE ANTI-INFLAMMATORY ACTIONS OF A CLONIDINE-LIKE IMIDAZOLINE ANALOGUE
Abstract
The initial studies of the present investigation indicated that only the formamidine pesticide chlordimeform (CDM) and cyproheptadine, an agent with antihistaminic and antiserotonergic properties, produced significant antagonism of the early phase of carrageenin-induced swelling, of an anaphylactoid-type paw swelling (albumin-induced), and of the swelling produced by direct injection of histamine or serotonin. CDM, aspirin, and SC-19220, a specific PG antagonist, produced significant antagonism of the later phase (three hour) of carrageenin edema. Therefore, these results indicated that CDM possesses a unique spectrum of acute anti-inflammatory activity not shared by either antihistaminic or antiserotonergic agents, or agents which affect the PG system. Moreover these results coupled with earlier studies showing low gastric ulcerogenicity by CDM suggested that it may be a prototype for a new structural class of anti-inflammatory agents. Because of reported carcinogenicity of metabolites of CDM, "hybrids" of CDM and the antihypertensive agent, clonidine (Catapres('(REGTM))), were screened for the CDM-like profile of activity in the second part of this study. Both CDMI {2-(2-methyl-4-chlorophenylamino)-2-imidazoline} and DCPI {2-(3,4 dichlorophenylanino)-2-imidazoline} produced anti-inflammatory activity and little gastric ulcerogenicity. Therefore, the structural replacement of the formamidine group by the imidazoline group did not result in any loss of desirable activity. Interestingly, clonidine also produced anti-inflammatory activity. CDMI was chosen as the most promising prototype drug and was further evaluated in the third part of this study. The anti-inflammatory activity of CDMI was dose-related following i.p,, oral, or intraventricular (i.c.v.) administration. The concentrations which were effective by i.c.v. injection were without effect when administered by either systemic route. Thus, it appeared that part of the mode of anti-inflammatory activity by CDMI was mediated centrally. Several possibilities for this central activity were investigated. When the i.c.v. IC(,50) (the concentration producing 50% decrease in carrageenin swelling) was administered to adrenalectomized rats, the anti-inflammatory activity was absent. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of school.) UMI
Degree
Ph.D.
Subject Area
Pharmacology
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