Author/Editor		Čarman-Kržan, Marija; Bavec, Aljoša; Zorko, Matjaž
Title		Molecular characterization of specific H1-receptor agonists histaprodifen and its Nalpha-substituted analogues on bovine aortic H1-receptors
Type		članek
Source		Naunyn Schmiedebergs Arch Pharmacol
Vol. and No.		Letnik 367, št. 5
Publication year		2003
Volume		str. 538-46
Language		eng
Abstract		We determined the molecular properties of the selective and potent H1-receptor agonist histaprodifen and its Na substituted analogues: methyl-, dimethyl-, and imidazolylethyl-histaprodifen (suprahistaprodifen). All derivatives show high affinity for 3H-mepyramine labeled bovine aortic H1-receptor binding sites with the following order of potency: suprahistaprodifen > dimethylhistaprodifen > methylhistaprodifen > histaprodifen > histamine. Suprahistaprodifen and dimethylhistaprodifen were the most potent displacers of 3H-mepyramine binding (Ki=4.3 and 4.9 nM, respectively). Histaprodifen, methylhistaprodifen and suprahistaprodifen binding was differentially influenced by GTP, whereas dimethylhistaprodifen was not affected. All drugs, except dimethylhistaprodifen, were activators of G-proteins. Their order of potency was suprahistaprodifen > histamine > histaprodifen > methylhistaprodifen. Their effect on G-protein activation was abolished by the addition of the H1-receptor antagonist triprolidine (10 microM), which given alone did not activate G-proteins. Our data suggest that histaprodifens are potent but heterogeneous H1-receptor ligands with diverse effects on the molecular level in our model system. While the histaprodifen, methylhistaprodifen and suprahistaprodifen data are in agreement with their agonistic nature, as shown in the functional studies performed on different species (rat and guinea pig H1-receptor), dimethylhistaprodifen behaved as an antagonist in our study.
Descriptors		AORTA RECEPTORS, HISTAMINE H1 BINDING SITES PYRILAMINE TRIPROLIDINE CATTLE GUANOSINE TRIPHOSPHATE GTP-BINDING PROTEINS BINDING, COMPETITIVE RADIOLIGAND ASSAY GTP PHOSPHOHYDROLASE