39739-51-0Relevant articles and documents
Synthesis and Histamine H1 Receptor Agonist Activity of a Series of 2-Phenylhistamines, 2-Heteroarylhistamines, and Analogues
Leschke, Christian,Elz, Sigurd,Garbarg, Monique,Schunack, Walter
, p. 1287 - 1294 (2007/10/02)
New histamine derivatives characterized by a (substituted) aryl, heteroaryl, benzyl, or hetroarylmethyl 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 agonist 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-ethanamine (39)) was significantly more potent than histamine (39: pD2 = 6.81, relative activity = 128percent).The 2-substituted histamine analogues were potential 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 concentraction-dependently by the H1 receptor antagonist mepyramine, yielding KB values for mepyramine in the nanomolar range.In vitro compounds 35 and 39 bound to 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 mepyramine to mouse cerebral cortex in vivo , thereby indicating that these histamine derivatives are not able to penetrate the blood-brain berrier.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:α1), 708 (H1:β1) 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.
Histamine analogues. 33rd communication: 2-phenylhistamines with high histamine H1-agonistic activity
Zingel, V.,Elz, S.,Schunack, W.
, p. 673 - 680 (2007/10/02)
2-Phenylhistamines with various substituents at the phenyl ring were synthesized and the influence of substitution in ortho, meta or para position on histamine H1-agonistic activity was investigated.Compounds with high activity occured in the meta phenyl series.Increased activity in the guinea-pig ileum assay was achieved by monosubstitution with halogen on the phenyl ring. 2-ethanamine (12) is the most potent highly selective H1-agonist known so far, showing 87percent relative potency compared with histamine and full efficacy at theH1-receptor.Relative activities of the 3-chloro analogue (11) and the 3-methyl analogue (13) are 81percent and 29percent, respectively.Histamine H2-activity could not be detected. 2-Phenylhistamines are available via reaction of the corresponding benzimidates with 2-oxo-4-phthalimido-1-butyl acetate (6) in liquid ammonia.
