Effects of a new sigma ligand, JO 1784, on cysteamine ulcers and duodenal alkaline secretion in rats

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 104; no. 2; p. 427
• Main Authors: Pascaud, X B, Chovet, M, Soulard, P, Chevalier, E, Roze, C, Junien, J L
• Format: Journal Article
• Language: English
• Published: United States 01.02.1993
• Subjects: Animals; Bicarbonates - metabolism; Cinnamates - pharmacology; Cyclopropanes - pharmacology; Cysteamine; Duodenal Ulcer - prevention & control; Duodenum - drug effects; Duodenum - metabolism; Gastric Acid - metabolism; Guanidines - pharmacology; Male; Rats; Rats, Sprague-Dawley; Receptors, sigma - drug effects; Stomach Ulcer - prevention & control
• ISSN: 0016-5085
• DOI: 10.1016/0016-5085(93)90410-E

The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-yl amine, hydrochloride], a new specific and highly selective sigma ligand, were examined in rats. Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied. JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784. These results show that JO 1784, a selective sigma ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.