Abstract
Objective and design: The putative partial H-1-receptor agonism of some H-3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. Methods: Whole segments of guinea-pig ileum were mounted in Tyrode's solution under isotonic conditions in the presence of atropine (10(-7) M) and were cumulatively treated with histamine as an ...
Abstract
Objective and design: The putative partial H-1-receptor agonism of some H-3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. Methods: Whole segments of guinea-pig ileum were mounted in Tyrode's solution under isotonic conditions in the presence of atropine (10(-7) M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H-1-receptor agonists were added cumulatively to determine agonist potency (pEC(50)) and intrinsic activity (E-max) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H-1-receptor antagonists were incubated for 3-15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H-1 receptor (pK(P) or pA(2) value, respectively). Results: Several analogues of FUB 372 displayed low H-1-receptor affinities (pA(2) or pK(P) 4.2-5.5) except for a methyl benzoate derivative (pA(2) = 6.8 1, Schild plot slope unity). FUB 372, four ortho-substituted derivatives (R = F, CH3, OCH3, CF3), and ciproxifan were weak contractile agents (E-max 9-38 %, pEC(50) 4.73 - 5.68, histamine: 6.70) susceptible to antagonism by the H-1-antihistaminergic drug mepyramine (2 . 10(-9)-10(-7) M). Agonist potency and H-1-receptor affinity of these compounds did not correlate with the data of a set of H-1-histaminergic 2-phenylhistamines bearing the same substituents. Conclusions: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H-1-receptor agonists lacking a basic side chain.
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