Synthesis and antidiarrheal activity of N-(aminoiminomethyl)-1H-pyrrole-1-acetamides related to guanfacine.

A series of N-(aminoiminomethyl)-1H-pyrrole-1-acetamides, related to guanfacine, were prepared and tested for antidiarrheal activity in castor oil dosed rats. trans-N-(Aminoiminomethyl)-2,5-dihydro-2,5-dimethyl-1H-pyrrole-1-acetami de (2), in which the dichlorophenyl ring of guanfacine is replaced by 2,5-dimethyl-2,5-dihydropyrrole, showed potent antidiarrheal activity but possessed only minimal cardiovascular activity in rats.

5,6,7,8-Tetrahydroquinolines. 5. Antiulcer and antisecretory activity of 5,6,7,8-tetrahydroquinolinethioureas and related heterocycles.

A series of thioureas derived from 5,6,7,8-tetrahydroquinoline, 1,5-, 1,6-, and 1,8-naphthyridiness, pyrido[2,3-b]azepine, and 7-azaindoline has been prepared and tested for antisecretory activity in the pylorus-ligated rat and protective activity against gastric erosions caused by cold-restraint stress. The thioureas exhibit different structure-activity relationships from the corresponding 5,6,7,8-tetrahydroquinoline-8-thiocarboxamides and these relationships are discussed. The activity of the thioureas is less affected by structural differences than the corresponding thioamides although they probably have the same mode of action.

5,6,7,8-Tetrahydroguinolines. 4. Antiulcer and antisecretory activity of 5,6,7,8-tetrahydroquinolinenitriles and -thioamides.

A number of 5,6,7,8-tetrahydroquinoling-8-nitriles and -8-thioamides and related compounds have been found to be potent inhibitors of basal gastric secretion in the pylorus-ligated rat and to afford protection against gastric erosions induced in rats by cold-restraint stress. Molecular manipulation has proved useful in determining factors necessary for such activity and structure-activity relationships are discussed. It has been shown that the most necessary requirements for activity are a pyridine nitrogen with its available lone pair and a primary or secondary thioamide. Also desirable is a six-membered carbocyclic ring with relative freedom from steric hinderance around the 8 position.

The gastric antisecretory activity of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide).

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide) possesses potent gastric antisecretory activity in a number of animal species. It causes a marked inhibition in the volume and concentration of basal and chemically-stimulated gastric acid secretion in the conscious rat and guinea-pig, and of chemically-stimulated secretion in the anaesthetised cat, dog and monkey. Marked activity is also seen in conscious Heidenhain-pouch dogs, against secretion stimulated by betazole and gastrin tetrapeptide. In the pylorus-ligated rat preparation, the antisecretory effect of 30 mg/kg tiquinamide persists for 8-9 h. The possible mode of action of this drug, in view of its wide non-selective antisecretory profile, is discussed.

The gastrointestinal and autonomic effects of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide).

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide), a potent gastric anti-secretory compound, affords good protection against stress- and chemically-induced gastric and duodenal erosions. It causes a dose-related delay in gastric emptying and intestinal transit, and does not have a primary effect on gastric mucosal blood flow. The only actions of tiquinamide on the peripheral autonomic nervous system are weak, but apparently specific, histamine H2-receptor blocking activity, and non-competitive inhibition of acetylcholine and histamine responses at 10(-3) mol/l. Since no other effect on isolated tissues can be detected, it seems unlikely that the antisecretory action of tiquinamide involves a direct action on the peripheral autonomic nervous system.