Unexpected partial H1-receptor agonism of imidazole-type histamine H3-receptor antagonists lacking a basic side chain.
OBJECTIVE
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 pA2 value, respectively).


RESULTS
Several analogues of FUB 372 displayed low H1-receptor affinities (pA2 or pKP 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.
Sadek
B
B
Faculty of Pharmacy & Health Sciences, Ajman University of Science & Technology, Al-Ain Campus, Al-Ain, United Arab Emirates.
Elz
S
S
Pertz
H H
HH
Stark
H
H
Schunack
W
W
D000818:Animals; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; C417965:proxyfan; C115705:ciproxifan; C029899:imidazole