Gastric antisecretory and pharmacologic properties of N,N-dimethyl-N'-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyridyl)ur ea (L-634,366).

N,N-Dimethyl-N'-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyridyl)urea (L-634,366) was selected from a series of pyridylurea compounds with antisecretory activity as a potential therapeutic agent for the treatment of ulcer disease. L-634,366 was an effective inhibitor of gastric secretion evoked by gastrin, histamine and 2-desoxy-D-glucose (2-DG) in conscious dogs. Orally, L-634,366 was slightly less potent than the reference H2 receptor blocker, cimetidine as an inhibitor of secretion evoked by histamine, but was equipotent as an inhibitor of secretion evoked by gastrin and 2-DG. In vitro L-634,366 was a weak antagonist of histamine (H2) receptor responses in the guinea-pig atria and rat uterus; in the atria the antagonism appeared to be noncompetitive. In the anesthetized dog, L-634,366 possessed weak anticholinergic activity as compared to atropine in reducing vagally mediated cardiovascular, antral motor responses and with regard to antagonizing the pressor response to the muscarinic stimulant, McN 343-A. The anticholinergic activity of L-634,366 was lower and more selective than that of pirenzepine or atropine in producing mydriasis in mice, in antagonizing acetylcholine induced bradycardia in guinea-pig atria, methacholine and acetylcholine elicited contractions in the guinea-pig ileum and QNB binding to muscarinic receptors. L-634,366, like carbenoxolone, increased incorporation of 3H-glucosamine in gastric mucous indicating an increase in synthesis or turnover of mucous. L-634,366 is a novel compound possessing a broad spectrum of antisecretory activity; in vitro studies suggested a weak noncompetitive inhibition of the histamine-H2 receptor in atria.