TY - JOUR
T1 - Unexpected partial H1-receptor agonism of imidazole-type histamine H3-receptor antagonists lacking a basic side chain
AU - Sadek, B.
AU - Elz, S.
AU - Pertz, H. H.
AU - Stark, H.
AU - Schunack, W.
PY - 2004/8
Y1 - 2004/8
N2 - 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 (Emax) 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 (pKP 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 (Emax 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.
AB - 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 (Emax) 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 (pKP 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 (Emax 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.
KW - Ciproxifan
KW - Guinea-pig ileum
KW - Histamine H-receptor agonists
KW - Histamine H-receptor antagonists
KW - Imoproxifan
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U2 - 10.1007/s00011-004-0351-8
DO - 10.1007/s00011-004-0351-8
M3 - Article
C2 - 15338060
AN - SCOPUS:4344631407
SN - 1023-3830
VL - 53
SP - S109-S115
JO - Inflammation Research
JF - Inflammation Research
IS - SUPPL. 2
ER -