SYNTHESIS AND HISTAMINE H-1 RECEPTOR AGONIST ACTIVITY OF A SERIES OF 2-PHENYLHISTAMINES, 2-HETEROARYLHISTAMINES, AND ANALOGS

New histamine derivatives characterized by a (substituted) aryl, heter oaryl, benzyl, or heteroarylmethyl substituent in the C2 position of t he imidazole ring have been prepared from appropriate imidates or amid ines, respectively, and 2-oxo-4-phthalimido-1-butyl acetate (1). The c ompounds were screened as potential H-1 receptor agonists on the isola ted guinea pig ileum. The 3-halogenated 2-phenylhistamines (halogen = Br (35) and I (36)) were equipotent with histamine, while 2-(3-(triflu oromethyl)phenyl)histamine trifluoromethyl)phenyl)1H-imidazol-4-yl]eth anamine (39)) was significantly more potent than histamine (39: pD(2) = 6.81, relative activity = 128%). The 2-substituted histamine analogu es were partial H-1 receptor agonists on the endothelium-denuded isola ted guinea pig aorta with pEC(50) values generally smaller than observ ed 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, re spectively, could be blocked concentration-dependently by the H-1 rece ptor antagonist mepyramine, yielding Kg values for mepyramine in the n anomolar range. In vitro compounds 35 and 39 bound to [H-3]mepyramine- labeled guinea pig cerebellar membranes with a pK(i) of 6.1 and 5.9, r espectively. However, upon iv administration, 35 (3-100 mg/kg) and 39 (3-300 mg/kg) failed to inhibit the binding of [H-3]mepyramine to mous e cerebral cortex in vivo, thereby indicating that these histamine der ivatives are not able to penetrate the blood-brain barrier. In functio nal in vitro studies on histamine H-2, H-3, and other neurotransmitter receptors the selectivity of 39 was found to be 2138 (H-1:H-2), > 64 (H-1:H-3), 1000 (H-1:M(3)), 105 (H-1:alpha(1)), 708 (H-1:beta(1)), and 71 (H-1:5HT(2A)). Thus compound 39 is the most potent and selective H -1 receptor agonist reported so far. These results make meta- substitu ted 2-phenylhistamines, especially 2-(3-(trifluoromethyl)phenyl)- and 2-(3-bromophenyl)histamine (39 and 35, respectively) valuable experime ntal tools for the selective stimulation of histamine H-1 receptors an d the study of H-1 receptor-mediated functions.