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.

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.

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.

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.