Structure-activity relationship of imidazolidine derivatives related to clonidine at histamine H2-receptors in guinea-pig isolated atria.

1 Cumulative concentration-response relationships for the chronotropic effects of histamine, oxymetazoline, clonidine and thirteen clonidine-like imidazolidine derivatives were examined in isolated spontaneously beating guinea-pig atria.2 The following compounds induced positive chronotropic effects: histamine, clonidine (2,6-dichloro-phenyliminoimidazolidine) and the 2,6-dibromo, 2,6-dimethyl, 2,6-diethyl, 2,6-dihydroxy, 2,4,6-trimethyl, 3,4-dihydroxy and 2-methyl-5-fluoro analogues of clonidine. These compounds appeared to act as partial agonists on histamine H(2)-receptors, with potencies ranging from one tenth to one hundredth and intrinsic activities from approximately 20% to 75% of those of histamine.3 The following compounds did not induce positive chronotropic effects but rather decreased the atrial rate, usually at high concentrations: oxymetazoline and the 2,3-dichloro, 4-dichloro, 5-dichloro, 2-chloro-4-methyl, 2-methyl-5-chloro, 2,4,6-trichloro analogues of clonidine.4 The effects of histamine were antagonized by cimetidine, the pA(2) value being 6.68 (s.e. mean = 0.16, n = 3), and also in a concentration-dependent manner by clonidine. Cimetidine antagonized the response to clonidine in a concentration-dependent manner; however, high concentrations of cimetidine depressed the maximal response to clonidine and the slope of the concentration-response curve was no longer parallel to the control curve.5 The effects of the other compounds which induced positive chronotropic effects were also antagonized by cimetidine (1 mumol/l); however, the effect of the 3,4-dihydroxy derivative was unaffected by cimetidine (1 mumol/l) but was abolished by propranolol (0.3 mumol/l).6 In general, phenyliminoimidazolidine derivatives with 2,6-substitution on the phenyl ring are active on histamine H(2)-receptors, whereas derivatives with 2,3-, 2,4- or 2,5-substitutions are weakly active or inactive. Thus the restriction imposed on the free rotation of the phenyl ring about the carbon-imino nitrogen bond by the introduction of two ortho substituents appears to result in increased agonist activity on the histamine H(2)-receptor. The introduction of substituents in the 3, 4 or 5 positions in the phenyl ring may lead to compounds sterically hindered from combining with the histamine H(2)-receptor.7 There is no apparent relationship between the activities of clonidine-like imidazolidine derivatives as agonists on histamine H(2)-receptors and their hypotensive activities (as reported in the literature).