New histamine derivatives characterized by a (substituted) aryl, heteroaryl, benzyl, or heteroarylmethyl substituent in the C2 position of the imidazole ring have been prepared from appropriate imidates or amidines, respectively, and 2-oxo-4-phthalimido-1-butyl acetate (1). The compounds were screened as potential H1 receptor agonists on the isolated guinea pig ileum. The 3-halogenated 2-phenylhistamines (halogen = Br (35) and I (36)) were equipotent with histamine, while 2-(3-(trifluoromethyl)phenyl)histamine (2-[2-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl]ethanamine (39)) was significantly more potent than histamine (39: pD2 = 6.81, relative activity = 128%). The 2-substituted histamine analogues were partial H1 receptor agonists on the endothelium-denuded isolated guinea pig aorta with pEC50 values generally smaller than observed on the guinea pig ileum, but the rank order of potency was found to be similar. The contractile effects on guinea pig ileum and aorta, respectively, could be blocked concentration-dependently by the H1 receptor antagonist mepyramine, yielding KB values for mepyramine in the nanomolar range. In vitro compounds 35 and 39 bound to [3H]mepyramine-labeled guinea pig cerebellar membranes with a pKi of 6.1 and 5.9, respectively. However, upon iv administration, 35 (3-100 mg/kg) and 39 (3-300 mg/kg) failed to inhibit the binding of [3H]mepyramine to mouse cerebral cortex in vivo, thereby indicating that these histamine derivatives are not able to penetrate the blood-brain barrier. In functional in vitro studies on histamine H2, H3, and other neurotransmitter receptors the selectivity of 39 was found to be 2138 (H1:H2), > 64 (H1:H3), 1000 (H1:M3), 105 (H1:alpha 1), 708 (H1:beta 1), and 71 (H1:5HT2A). Thus compound 39 is the most potent and selective H1 receptor agonist reported so far. These results make meta-substituted 2-phenylhistamines, especially 2-(3-(trifluoromethyl)phenyl)- and 2-(3-bromophenyl)histamine (39 and 35, respectively) valuable experimental tools for the selective stimulation of histamine H1 receptors and the study of H1 receptor-mediated functions.