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Smooth muscle cells isolated from the longitudinal muscle layer of guinea pig ileum were used to determine the presence and type of cholecystokinin/gastrin receptor mediating contraction. This was accomplished with a series of cholecystokinin and gastrin agonists (CCK-8, des(SO3)CCK-8, gastrin-17, des(SO3)gastrin-17 and pentagastrin) and antagonists (glutaramic acid derivatives CR 1392, CR 1409, CR 1505 and proglumide). The order of potency of agonists based on EC50 values derived from concentration-response curves was: CCK-8 greater than des(SO3)CCK-8 greater than gastrin-17 greater than des(SO3)gastrin-17. The inhibitory dissociation constant (Ki) for the antagonist CR 1505 derived from Schild plots was the same whether sulfated CCK-8 or desulfated gastrin-17 was used as agonist (4.47 +/- 0.76 versus 4.68 +/- 0.78 nM). Pentagastrin acted as a partial agonist and inhibited partially the response to CCK-8. The Ki values determined for all antagonists with pentagastrin as agonist were similar to those with CCK-8 as agonist. The order of potency of agonists and the independence of Ki values from the type of agonist used implied that CCK and gastrin interact with one receptor type; the receptor is more sensitive to CCK-8 but is minimally influenced by sulfation of the tyrosine residue. In this respect, the receptor appears to be distinct from the CCK receptor on gallbladder muscle cells and pancreatic acinar cells.

The guinea-pig oesophageal muscularis mucosae was used to determine the affinity for muscarinic receptors of two new tricyclic compounds, DF 545 and DF 594, which are structurally related to pirenzepine. Both acetylcholine and bethanechol induced a concentration-dependent contraction of the muscularis mucosae. This contraction was competitively antagonized by DF 545 and DF 594 over the dose range 10(-7)-10(-5) M, while at higher concentrations both antagonists caused a depression of the maximal response to the cholinomimetics. The potency of DF 545 and DF 594 appeared to be comparable to that of pirenzepine and approximately 50 times lower than that of atropine. By comparing the affinities of DF 545 and DF 594 with those of selective antagonists (methoctramine and 4-DAMP) which discriminate between M2/M3 muscarinic receptor subtypes, it emerged that pirenzepine as well as DF 545 and DF 594 might act on M3 receptors, which seem to be predominant in the guinea-pig oesophageal muscularis mucosae. McN-A-343 exhibited no agonist activity while it acted as a competitive antagonist against acetylcholine and bethanechol. None of the compounds exhibited calcium antagonist properties. DF 545 inhibited the contractile responses to histamine, but DF 594 and pirenzepine did not.

The results of 2-aminohistamine (compound I) and 2-amino-5-methylhistamine (compound II) on cat acid secretion and on guinea pig gall-bladder motility are described and compared with those of Histamine or Dimaprit. The compound (I) showed a greater H2- than H1-receptor stimulating activity, while compound (II), inactive on H1, was effective on H2-receptors, being endowed with a less "potency" and "efficacy" than compound (I). The pharmacological activities of both compounds, related to their chemical structure, are discussed.

The influence of fentonium, a new derivative of hyoscyamine, on the gastric secretion has been evaluated in rats, cats and dogs. The compound appeared to be able to markedly reduce the gastric hypersecretion produced by pentagastrin, caerulein and bethanechol; its antagonizing activity against histamine stimulation was poor.

A new series of 3-methoxy-1,2-benzisothiazol-5-ylacetic acid analogs and some of their functional derivatives were synthesized and tested for their analgesic, antipyretic and anti-inflammatory activities. From an analysis of the relationship between structure and pharmacological activity, it was observed that modifications in the acid group induced useful variations in the parameters studied.

2-Amino- and 2-guanidinothiazole derivatives having in position 5 a methylthioalkyl side-chain with urea-equivalent moieties were prepared for comparison with H2-antagonists of cimetidine and tiotidine series. Examination of the pharmacological results obtained from experiments on guinea pig atria and in cat gastric fistula, suggests some general observations about the structure-activity relationship of the compounds synthesized. The activity trend of these products is different from that of H2-imidazole antagonists while it is similar to that of the tiotidine series. Unlike the tiotidine similar compounds, the 2-guanidino-5-thiazolyl derivatives are less potent than the corresponding 2-amino-5-thiazolyl products. The activity of the latter ones is reduced in comparison to that of tiotidine or cimetidine.

Dose-response curves of histamine were studied on the mesenteric circulation of the anaesthetized rat. The vasodilation produced by small doses of histamine was prevailingly H2-receptor-dependent, as shown by its inhibition by cimetidine but not by mepyramine, and by its reproducibility by some H2-receptor agonists, but not by specific H1-receptor agonists. The vasodilation produced by high doses of histamine was mainly due to stimulation of H1-receptors, as shown by its 70% inhibition by mepyramine. Mepyramine and cimetidine given simultaneously nearly completely inhibited the vasodilating action of high doses of histamine. Certain H2-receptor agonists, administered at high doses, induced a paradoxical vasoconstriction. It is suggested that a small number of H2-receptors is present in rat mesenteric arterioles, and that these receptors may play a physiological role in the control of mesenteric circulation.

The effects of cimetidine and ranitidine, alone or combined with sulglycotide or carbenoxolone, and those of 16,16-dimethyl prostaglandin E2 were investigated on mucosal lesions induced in pylorus-ligated rats. The drugs were administered orally after pylorus ligation; 3 hr later the animals were killed, the stomachs removed and examined for the presence of mucosal lesions. Volume, pH, total acidity, pepsin, free and barrier mucus were determined. H2-antagonists both at nonantisecretory and antisecretory doses failed to prevent gastric mucosal lesions or to affect significantly mucus and pepsin. Sulglycotide and carbenoxolone inhibited pepsin secretion, the latter enhanced barrier mucus and both reduced lesion severity. A nearly complete prevention of mucosal damage was observed after anti-secretory doses of cimetidine plus sulglycotide or carbenoxolone. Data obtained compared with those of 16,16-dimethyl prostaglandin E2 suggest that mucus and pepsin might have a partial role in ulcer prevention.

The synthesis and chemical and pharmacological properties of 3-benzyl-1,2-benzisothiazoleaminoalkyl derivatives are reported. These compounds were studied because 4-dimethyl-2-phenyl-2-(1,2-benzisotiazol-3-yl)-butyramide and N,N-dimethyl-3-phenyl-3-(1,2-benzisothiazol-3-yl)propylamine were recently found to have antispasmodic properties. Most of the compounds studied aspecifically inhibited the contracturant effects of acetylcholine, histamine and BaCl2. Three of them showed mixed antagonism (competitive and non-competitive) versus acetylcholine and histamine, showing both antimuscarinic and antihistaminic properties. However the antimuscarinic action prevailed over the others, as shown by pA2 and pD'2 calculated values. On the basis of the results obtained, the structure-activity relationships is discussed.

In the present study the effects of three structurally different H2-receptor antagonists (cimetidine, ranitidine and oxmetidine) have been investigated on gastric acid and pepsin secretion of eight cats provided with cannulated gastric fistulas. The maximum pepsin output obtained from a set of complete dose-response curves of dimaprit was not statistically different from basal values. In the presence of the H2-antagonists, while the gastric acid secretion induced by dimaprit was competitively antagonized, the pepsin secretion was differently affected. The data obtained on pepsin activity with cimetidine and ranitidine were quite similar to the control values. By contrast, oxmetidine induced a significant increase. The results suggest a very weak involvement of the H2-receptors in pepsin activity and that oxmetidine performance could not be attributable to an H2-receptor block.

This paper reports the synthesis of 2- and 4- [benzyl-(2-dimethylaminoethyl)amino]pyrimidine compounds and the evaluation of their inhibitory properties against histamine (H1), acetylcholine and barium chloride, on guinea pig isolated ileum. 4-[p.Methoxybenzyl-(2-dimethylaminoethyl)amino]-2-methoxy-pyrimidine (VIII) is shown to possess H1 receptor antagonist activity, with a potency similar to that observed for Tonzylamine. By contrast, a specific, although weak, antimuscarinic effect is displayed by 4-[benzyl-(2-dimethylaminoethyl)amino]-2-methoxy-5-methylthio-pyrimidine (XII).

In the present paper the authors describe the effects of Dimaprit analogs on guinea pig gastric mucosa "in vitro". This preparation, widely described by Holton and Spencer, is useful for studying the actions of stimulants and inhibitors which act directly on the oxyntic cells. Such compounds are weakly active as stimulants of H2-receptors and studied as antagonists fail in inhibiting acid secretion evoked by Dimaprit, the most specific H2-receptors agonist. In particular, the compound marked Ros 5 clarifies that the isothiourea group of Dimaprit simulates the amidine system only chemically but not pharmacologically. The different mechanism of Dimaprit and Histamine on H2-receptors has been discussed.

This paper describes the synthesis of 3-benzyl-1,2-benzisothiazole derivatives, structurally related to benzylisoquinolines, and their analgesic activity studied using writhing technique in the mouse. The presence of lipophilic substituents in position 3, 4 of the benzyl group give substances with analgesic activity, although their "potency" is lower than that shown by papaverine.

This paper describes the synthesis of 2- and 4-[benzyl-(2-dimethylaminoethyl)amino]pyrimidine compounds and their antihistaminic properties studied on isolated guinea-pig ileum. Calculated pA2 values show that the antihistaminic activity of 4-[p.methoxybenzyl-(2-dimethylaminoethyl)amino]pyrimidine is specific and potent (8-10 times higher than that of thonzylamine).

The synthesis of a new series of 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic compounds and some of their functional derivatives is described. The compounds, on the basis of data obtained from 1,2-benzisothiazolin-3-one derivatives, were biologically examined mainly for their antiphlogistic and analgesic actions. Results obtained, in analyzing the relationship between structure and pharmacological actions, suggest that both 4-(3-oxo-1,2-benzisothiazolin-2-yl)-phenyalkanoic acids and o-sulphobenzimido alkanoic esters are endowed with pain-killing effects comparable in potency and efficacy with phenylbutazone.

H2-receptor but not H1-receptor antagonists, administered by intravenous infusion, produce a dose-dependent constriction of superior mesenteric arterioles of the anaesthetized rat under resting conditions. However the possibility that this effect could be related to a blockade of H2 receptors is unlikely, since their potency on blood flow changes does not parallel known H2-receptor antagonist activity. Furthermore, the estimated potency ratio is not in the expected order if the vasoconstriction is due to H2-antagonism, the potency ratios on guinea-pig atrial muscle and on mouse gastric acid secretion being famotidine greater than oxmetidine greater than ranitidine greater than cimetidine.

Based on previous observations, the preparation, some physicochemical (partition coefficient, pKa) and pharmacological properties of 4-(3-oxo-1,2-benzisothiazolin-2-yl)alkanoic, benzoic, phenyl, phenoxyalkanoic acids and of some of their functional derivatives are reported. All new compounds were biologically examined for their antiphlogistic, analgesic and antipiretic actions, in comparison with those of 1,2-benzisothiazolin-2-one and with those of ibuprofen as the antiphlogistic, analgesic, antipyretic arylalkanoic prototype. Structure-activity relationships showed that the 1,2-benzisothiazolin-2-one and its new alkanoic and arylalkanoic derivatives have strong actions which are however specific for some of the tested pharmacological properties. From this point of view, the synthesized substances have a narrow spectrum of activity, if compared with ibuprofen which is at the same time an antiphlogistic, analgesic and antipiretic substance. The antiphlogistic and antipyretic activities of 4-(3-oxo-1,2-benzisothiazolin-2-yl)benzoic, phenylacetic and phenylmethylacetic acids and the antipyretic and analgesic actions of 3-oxo-1,2-benzisothiazolin-2-ylacetic acid, which are comparable or higher in "potency" than those of ibuprofen, are noteworthy.

In the present paper pharmacological properties studied on the gastrointestinal tract of two new alkylaminoalkylphenylbenzisothiazole derivatives, 4-dimethylamino-2-phenyl-2-(1,2-benzisothiazole-3-yl)butyramide (PM2) and N,N-dimethyl-3-phenyl-3-(1,2-benzisothiazole-3-yl)propylamine (PM3) have been reported. Both drugs showed antispasmodic effects on gastroduodenal junction of the anaesthetized rat stimulated by Caerulein, according to previous results obtained on guinea-pig isolated ileum. On this substrate they were different in the potency being PM3 more active than PM2. On the contrary, the hypersecretion induced by Histamine or Gastrin-17 in rat perfused stomach was potentiated by PM2 and inhibited by PM3. Similar effects were observed on guinea-pig "in vitro" stomach preparation where PM2 and Papaverine were ineffective in modifying Histamine dose-response curves and PM3 reduced significantly maximal peak effects of Histamine, behaving as a non-competitive antagonist. The significant differences observed on gastric secretion but not on other substrates, from compounds structural analysis, appear scarcely justified and seem to us important to be further investigated.

Antipyretic activity of new compounds, 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic acids, their esters, amides and 1,1-dioxide derivatives has been studied. The acid compound of the benzoic series (I:a), tested at graded doses, exerted a noticeable antipyretic action; it had two times the "potency" of benzisothiazolone but an almost equal "efficacy". Its "potency" however was not proportional to the development of gastric lesions and to the acute toxicity. A decreased pharmacological activity has been observed in phenylalkanoic acids in the following order: R = COOH greater than CH2COOCH greater than CH(CH3)COOH greater than CH(C2H5)COOH, probably due to their increasing lipophilic character. By contrast among 1,1-dioxide derivatives the most effective in preventing pyrogen-induced fever was the ethyl ester (V:c) of benzoic series which appeared to be as active as paracetamol. The interest arising from these observations is here after discussed.

A representative group of 2-aminothiazolylethylamine derivatives, in which the gastric acid secretion stimulating S-aminoalkylisothiourea moiety can be recognized, was tested. The quite different responses observed suggest that in vivo but not in vitro some events mimicking an H2-receptor agonist-like activity rather than a direct interaction with H2-receptors could take place. On the basis of structure-activity relationships, it can be speculated that the active conformation of dimaprit is not that resembled by these compounds which have been considered as cyclic models of one of its possible conformations.

Two selective H2 receptor stimulants (5-methyl-N-methylhistamine and dimaprit) so far never tested in isolated gastric preparations, were found to be strong stimulants of acid secretion from the guinea pig isolated gastric fundus. Although some differences were observed in the cumulative dose--response curves for these two agonists, the peak responses obtained were not significantly different from the maximum response to histamine. Cimetidine produced parallel displacement of the dose--response curves to the right with the maximum response unchanged, suggesting competitive antagonism of H2 receptors. The dose--response curve for histamine was not affected by the simultaneous administration of an H1 receptor agonist, 2(2-aminoethyl)thiazole, or of an H1 receptor antagonist, pyrilamine. This indicates that the action of histamine on the isolated guinea pig gastric fundus is associated exclusively with H2 receptor stimulation.

The effects of sulglicotide, alone or combined with cimetidine, have been investigated on mucosal lesions induced in rats by pylorus ligation. In the same animals, the measurement of acid and pepsin output and of soluble and barrier mucus has been performed. Dose-dependent sulglicotide prevented the development of mucosal lesions and its protective effect was achieved without significant modifications in gastric acid secretion. The secretion of pepsin and of mucus was markedly inhibited at every dosage of the compound. Neither the damage to gastric mucosa nor the secretion of acid, pepsin and mucus were affected by cimetidine. The combination of the highest doses of both compounds resulted in a synergistic gastro-protective effect, not dependent on a synergistic effect on the reduction in acid secretion.

A series of thiazole derivatives, in which a side-chain with different urea-equivalent groups was introduced in position 5 of the heterocycle, have been tested as inhibitors of dimaprit-induced gastric acid and pepsin secretion in the gastric fistula cat. By comparing the in vivo and the previously reported in vitro activity of these compounds, we can note a very close parallelism not only in the quality of their action but also in the estimates of pA2 values. These data support an interdependence between the molecular substructures and the affinity for the H2-receptor.

The H2-antagonist activity of thiazole derivatives, substituted on position 5 with urea-equivalent groups, has been tested on guinea-pig isolated atria stimulated by dimaprit. By comparing the activities of the 2,5-disubstituted thiazole derivatives with those of the corresponding 2,4-disubstituted derivatives it can be seen that the side-chain position is critical to activity and differently influences activity in the various series. The heteroaromatic ring atom sequence N-C-S-C-side chain is always associated with a low antagonist activity.

The pharmacological properties of 2-aminohistamine and 2-amino-5-methylhistamine were studied and compared with those of histamine, 5-methylhistamine and dimaprit. The introduction of an amino group in position 2 of the histamine imidazole ring caused a reduction of histamine potency, mostly with respect to H1 receptors. Such disactivation was much more evident in its corresponding 5-methyl derivative. The pharmacological activity related to the chemical structure will be discussed in the paper.

In the present paper the gastric secretory and motor responsiveness to a gastrin-like peptide, caerulein, was assessed in rats with a chronic gastric ulcer induced by 'isolation', 48 h after completing prolonged treatments (30 and 60 days) with cimetidine (80 and 160 mg/kg), pirenzepine (8 and 16 mg/kg) and sulglycotide (160 mg/kg) administered orally as a single daily dose. After a 30 day pretreatment with both doses of cimetidine, gastric acid secretion was inhibited and the pylorus spasmogenic activity induced by caerulein was enhanced. The gastric effects of the peptide were not modified by pirenzepine pretreatment while an antisecretory action was shown by sulglycotide after the completion of prolonged treatment (60 days). The ulcers were significantly reduced by cimetidine (low dose) and sulglycotide after 30 day pretreatment. The effects are more likely to be related to the treatment than to the presence of the drugs on gastric receptors.

As a part of a study on H2-agonists, the preparations and properties are reported for a representative group of 2-aminothiazolethylamine derivatives which contain the gastric secretion stimulating S-aminoalkylisothiourea moiety. The test compounds were obtained by known methods or from 2-(2-amino-5-thiazolyl)ethyl chloride and were tested for their possible histamine-like activities on different biological substrates. From the biological results it appears that the behaviour of the substances is rather complex, but the following general observations can be pointed out: the contracturant properties, sometimes quite marked, do not derive from direct H1-specific activities; the effects, particularly evident in stimulating in vitro or in vivo gastric secretion, in relaxing gall-bladder smooth muscle, on auriculae and/or on blood pressure, are not competitively antagonized by cimetidine; none of the tested compounds proved to be an antagonist of histamine H2-receptors, while one of them is found to inhibit competitively the H1-receptors. On the basis of structure-activity relationships it can be excluded that the iuxta-nuclear NH2 group of 2-aminothiazolethylamines reacts, in some way, with the H2-receptors, since, in this case, the 2-aminothiazole group is not a pharmacophore like the 2-aminoimidazole or isothiurea group. Consequently the hypotheses, that the flexibility of the molecule is a fundamental requirement for the H2-stimulating properties of S-(3-dimethylaminopropyl)isothiurea and that the different activities of 2-aminohistamine, in comparison with those of 2-methylhistamine, are due to the existence of a hydrophilic area suitable for the allocation of the iuxta-nuclear NH2 group in the H2-receptor, are strengthened.

The effects of pirenzepine on gastric and duodenal ulceration and barrier mucus levels, as well as on changes of superior mesenteric artery diameter caused by cysteamine, were investigated in rats and compared with those of atropine. Cysteamine induced severe gastric and duodenal ulcers and decreased both barrier mucus levels and mesenteric blood flow. Pirenzepine reduced gastric and duodenal ulceration induced by cysteamine. Moreover, pirenzepine significantly increased basal mesenteric artery diameter and fully prevented cysteamine-induced decrease in mesenteric blood flow. Under the same conditions, atropine failed to prevent gastric and duodenal ulceration or mesenteric artery changes caused by cysteamine. Both pirenzepine and atropine were without any effect on cysteamine-induced inhibition of gastric and duodenal barrier mucus levels. The present results are consistent with the view that pirenzepine protects against gastroduodenal ulceration caused by cysteamine by increasing blood flow at the level of the ulcerated mucosa. The higher affinity of pirenzepine for the muscarinic receptors of sympathetic ganglia may explain the difference between the effects of pirenzepine and atropine. In addition to this, the measurement of superior mesenteric artery diameter changes may represent an accurate and reproducible method, suitable for studying the gastrointestinal protective mechanisms of the drugs.

Different doses of the new chemically stable PGE2 analogue, FCE 20700, (150, 300, 450, 900, 1200 and 1800 micrograms kg-1) and of 16,16-dimethyl PGE2, DMPGE2, (1, 3, 10, 30 and 100 micrograms kg-1) were administered by gavage to pylorus-ligated rats. The dose-response relationship in preventing gastric mucosal damage and in inhibiting gastric acid and pepsin secretion was investigated. In the same animals, a simultaneous evaluation of barrier and luminal mucus was also performed. Both compounds were markedly active in preventing the macroscopic damage of the gastric mucosa and, at higher doses, in inhibiting gastric acid secretion. FCE 20700 was approximately 100-150 times less potent than DMPGE2. Mucosal protection appeared to be exerted by the two prostaglandins independently of any action on mucus. Furthermore, as the antisecretory doses were approached, a decline in protective activity became evident, suggesting that the dosage of prostaglandins is critical, making it possible to orient their activity either towards mucosal protection or towards acid inhibition.

The effects of some imidazole derivatives, H2-antagonists and H2-agonists, with different alkyl groups in 5-position (R = Me, Et, i.Pr), were studied comparatively on cat gastric secretion and guinea-pig gastric fundus. The antagonistic and agonistic activities decrease with increase in the substituent inductive effect, and, in particular, it should be noted that the cimetidine ethyl analog (compound V) is a competitive antagonist of H2-histamine receptors. More hypotheses on the H1- and H2-receptor surfaces are proposed.

Two series of experiments were performed on rat chronic ulcer in order to assess the possible curative and mucosal protective properties of 2 week treatments, or the preventive properties of 4 week treatments with antisecretory agents, acting with different mechanisms of action. At the end of the treatments the gastric secretory and motor responsiveness to a gastrin-like stimulus was simultaneously evaluated. The results support the view that antimuscarinic agents as well as H2-blockers cannot be defined as protective and that after a 4 week treatment they can induce modifications of gastric functions.

Carbenoxolone was administrated, by intubation per os, to guinea-pigs, then the animals were killed 2 and 4 hours later. In perfusion experiments, carbenoxolone was injected for 5,10 and 20 min respectively. The results show a decreased uptake of formiate-H3 into RNA and DNA in vivo. During perfusion of stomach, CBO causes a precocious enhancement of specific radioactivity of nucleic acids, then a decrease was observed. The pattern of polyamines in perfused stomach shows an increased uptake of putrescine-C14 into spermidine. Finally, the specific radioactivity of proteins was enhanced in vivo and in vitro by CBO. The results demonstrate that the drug alterates the proliferative cell cycle and induces the synthesis of proteins.