2,3,4,5-Tetrahydro-5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-1H-pyrido[4,3-b]indol-1-one hydrochloride

Description

Alosetron was launched in March 2000 in the US as a new oral treatment for diarrheapredominant irritable bowel syndrome in women. This structurally-related analog of ondansetron is prepared by alkylation of the pyrido[4,3-b]indol-1-one skeleton with the appropriate trityl-protected chloromethylimidazole. Although its mechanism of action is not fully understood, alosetron is known to be a potent and selective 5-HT₃ antagonist with a superior pharmacodynamic profile than its predecessor ondansetron. Besides being present in the central nervous system, 5-HT₃ receptors are located on neurons of both enteric and sensory nervous systems. Alosetron may act on several of these sites leading to the regulation of intestinal secretion, gastrointestinal contractility and gastric emptying. Clinically, it has been found that a twice-daily dose of Img of alosetron not only improves bowel function, stool frequency and stool consistency but also affects the pain severity and sense of urgency in IBS. Despite its short half-life (1.5h) and extensive metabolism (at least 12 metabolites have been identified in urine), alosetron shows a long duration (10h) of inhibition of the serotonin-induced skin flare response in man. Due to reported cases of constipation and ischemic colitis as well as rare fatalities of patients under treatment with Lotronex, Glaxo-Wellcome withdrew the drug from the US market in November and is currently running further clinical trials.

Originator

Glaxo-Wellcome (UK)

brand name

Lotronex

Biological Activity

Alosetron(GR68755)Hydrochloride(1:X) is a potent and selective 5-HT3 receptor (5-HT3receptor) antagonist. AlosetronHydrochloride(1:X) for the study of irritable bowel syndrome (IBS). AChemicalbooklosetronHydrochloride (1:X) blocks 5HT3-mediated rapid depolarization of guinea pig intermuscular and submucosal neurons with IC50 at ~55nM. AlosetronHydrochloride (1:X) attenuates visceral nociceptive effects of rectal distension in awake or anesthetized dogs. Has anti-inflammatory activity.

in vivo

Dexamethasone and Alosetron-treated (1 mg/kg; ip; daily for 6 days) rats exhibits a significant decrease in the diarrhea index, in comparison with TNBS-control group, especially after the initial 2 days of treatment following the induction of colitis.