FUB-407

(R)‐α‐methylhistamine, a selective agonist of histamine H3 receptors, promotes mucus secretion and increases the number and volume of mucus‐secreting cells. The hypothesis that the increased number of mucous cells could reside in an alteration of homeostasis in the gastric epithelium was investigated.(R)‐α‐methylhistamine was administered to rats 1 h (10–100 mg kg−1 by intragastric and by intraperitoneal route) and 24 h (100 mg kg−1 by intragastric route) prior to killing. The (S)‐isomer of α‐methylhistamine (55.4 mg kg−1), 100 times less potent than the (R)‐isomer at H3 receptors, and the H3‐receptor agonist FUB 407 (9.14–91.35 mg kg−1) were intragrastically administered 1 h prior to killing. The H1‐receptor antagonist mepyramine (30 mg kg−1), the H2‐receptor antagonist famotidine (3 mg kg−1), and the H3‐receptor antagonists ciproxifan (3 mg kg−1) and clobenpropit (30 mg kg−1) were intragastrically administered 30 min before (R)‐α‐methylhistamine. Gastric tissue was processed for histology and immunohistochemistry.Within 1 h, (R)‐α‐methylhistamine and FUB 407 dose‐dependently increased the number of BrdU‐positive cells and of apoptotic cells. (S)‐α‐methylhistamine failed to modify proliferation and apoptosis. The increase in proliferation by (R)‐α‐methylhistamine was reversed by ciproxifan and clobenpropit, but not by mepyramine and famotidine.(R)‐α‐methylhistamine accelerated the differentiation towards pit cells and their outward migration 24 h after its administration. These effects were counteracted by ciproxifan. The apoptosis rate was unaffected at 24 h.These findings reveal a primary role of histamine H3‐receptor ligands in modulating cell proliferation and migration in rat fundic mucosa.British Journal of Pharmacology (2002) 137, 237–244. doi:10.1038/sj.bjp.0704853

The ability of the H₃-receptor agonists and the pro-drug of α-methylhistamine to protect the rat gastric mucosa against damage by 0.6N HCl was evaluated.The histamine homolog impentamine, reported to display both partial agonist and antagonist properties, was also evaluated.The intragastric administration of (R)α-methylhistamine, its prodrug BP 2.94, and FUB 407 was shown to markedly reduce the formation of macroscopically evident gastric lesions produced by concentrated acid.Conversely, imetit, immepip and impentamine failed to modify the damaging effect of the concentrated acid.These results provide evidence that gastroprotection is selectively produced by (R)α-methylhistamine, its prodrug and FUB 407, but not by imetit and immepip.The latter compounds, classified as H₃-receptor agonists, appear to discriminate between functional models, in that they express different pharmacol. behavior at H₃-receptors present in central and peripheral systems to those receptors responsible for gastroprotection.