(R)-(-)-α-Methylhistamine dihydrobromide

Histamine induces cytoskeletal changes in human eosinophils via the H(4) receptor.[Pubmed:14530216]

Br J Pharmacol. 2003 Nov;140(6):1117-27.

1. Histamine (0.004-2 microm) induced a concentration-dependent shape change of human eosinophils, but not of neutrophils or basophils, detected as an increase in forward scatter (FSC) in the gated autofluorescence/forward scatter (GAFS) assay. 2. The histamine-induced eosinophil shape change was completely abolished by thioperamide (10 microm), an H3/H4 receptor antagonist, but was not inhibited by pyrilamine or cimetidine (10 microm), H1 and H2 receptor antagonists, respectively. The H4 receptor agonists, clobenpropit and clozapine (0.004-2 microm), which are also H3 receptor antagonists, both induced eosinophil shape change, which was inhibited by thioperamide (10 microm). The H3/H4 receptor agonists, imetit, R-alpha-methyl histamine and N-alpha-methyl histamine (0.004-2 microm) also induced eosinophil shape change. 3. Histamine induced actin polymerisation (0.015-10 microm), intracellular calcium mobilisation (10-100 microm) and a significant upregulation of expression of the cell adhesion molecule CD11b (0.004-10 microm) in eosinophils, all of which were inhibited by thioperamide (10-100 microm). In addition, the H4 receptor agonist/H3 receptor antagonist clozapine (20 microm) stimulated a rise in intracellular calcium in eosinophils. 4. Activation of H4 receptors by histamine (1 microm) primed eosinophils for increased chemotactic responses to eotaxin, but histamine (0.1-10 microm) did not directly induce chemotaxis of eosinophils. 5. Pertussis toxin (1 microg ml-1) inhibited shape change and actin polymerisation responses induced by histamine showing that these effects are mediated by coupling to a Galphai/o G-protein. 6. This study demonstrates that human eosinophils express functional H4 receptors and may provide a novel target for allergic disease therapy.

Characterization of histamine H3-receptors in guinea-pig ileum with H3-selective ligands.[Pubmed:1963802]

Br J Pharmacol. 1990 Nov;101(3):621-4.

1. The effect of the selective histamine H3-receptor agonist R-(alpha)-methylhistamine has been investigated on the contractile responses of the longitudinal smooth muscle of guinea-pig ileum elicited by electrical field stimulation of acetylcholine release from myenteric nerve endings. 2. R-(alpha)-methylhistamine produced a concentration-dependent (EC50 = 1.4 +/- 0.2 x 10(-8) M) inhibition of the response to electrical field stimulation which was insensitive to inhibition by mepyramine (1 microM) and tiotidine (2.4 microM). 3. This response to R-(alpha)-methylhistamine could be inhibited in a competitive fashion by a range of H3-receptor antagonists including thioperamide (KB = 1.1 nM), impromidine (KB = 65 nM), norburimamide (KB = 380 nM) and SKF 91486 (KB = 34 nM). Burimamide was also a potent inhibitor of this response but the Schild slope obtained (1.3) was significantly greater than unity. 4. The estimated KB values were all within a factor of three of those values reported for the histamine H3-receptor mediating inhibition of histamine release in rat cerebral cortex. 5. These data suggest that the histamine receptor mediating inhibition of cholinergic neurotransmission by R-(alpha)-methylhistamine in guinea-pig ileum is the same as the H3-receptor present in rat cerebral cortex.

Effects of the histamine H3-agonist (R)-alpha-methylhistamine and the antagonist thioperamide on histamine metabolism in the mouse and rat brain.[Pubmed:2540269]

J Neurochem. 1989 May;52(5):1388-92.

To study the feedback control by histamine (HA) H3-receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H3-agonist, (R)-alpha-methylhistamine, and an H3-antagonist, thioperamide, on the pargyline-induced accumulation of tele-methylhistamine (t-MH) in the brain of mice and rats were examined in vivo. (R)-alpha-Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady-state t-MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline-induced increase in the t-MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline-induced t-MH accumulation by approximately 70% 1 and 2 h after treatment. Lower doses of (R)-alpha-methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline-induced t-MH accumulation in the mouse brain. In the rat, (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline-induced t-MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.

(R)-(-)-α-Methylhistamine dihydrobromide is a potent and selective H3 histamine receptor agonist with a Kd of 50.3 nM. (R)-(-)-α-Methylhistamine dihydrobromide can cross the blood-brain barrier, and can enhance memory retention, attenuates memory impairment in rats.

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