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Iodoproxyfan, i.e., 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether, is a novel potent and selective histamine H3 receptor antagonist. [125I]Iodoproxyfan binding to membranes of the rat striatum was reversible and saturable. Specific binding defined with 1 microM (R)-alpha-methylhistamine corresponded to 65% of the total at 30 pM. Scatchard analysis indicated a Kd of 65 pM and maximal binding capacity of 78 fmol/mg of protein. The specificity of [125I]Iodoproxyfan binding to H3 receptors was demonstrated by its pharmacological profile. A series of H3 receptor agonists inhibited [125I]iodoproxyfan binding with a similar maximal effect and with the expected order of potency and stereoselectivity ratio. H3 receptor antagonists inhibited the specific binding with the expected Ki values. In the presence of guanylnucleotides, 40% of sites exhibited a approximately 40-fold lower affinity for histamine, indicating that …