Unexpected partial H₁-receptor agonism of imidazole-type histamine H₃-receptor antagonists lacking a basic side chain

Objective and design: The putative partial H₁-receptor agonism of some H₃-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 H₁-receptor agonists were added cumulatively to determine agonist potency (pEC₅₀) and intrinsic activity (E_max) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H₁-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 H₁ receptor (pK_P or pA ₂ value, respectively). Results: Several analogues of FUB 372 displayed low H₁-receptor affinities (pA₂ or pK _P 4.2-5.5) except for a methyl benzoate derivative (pA₂ = 6.81, 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%, pEC₅₀ 4.73-5.68, histamine: 6.70) susceptible to antagonism by the H₁- antihistaminergic drug mepyramine (2·10^-9-10^-7 M). Agonist potency and H₁-receptor affinity of these compounds did not correlate with the data of a set of H₁-histaminergic 2-phenylhistamines bearing the same substituents. Conclusions: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H₁-receptor agonists lacking a basic side chain.