Muscarinic M1 and M3 receptor antagonist effects of a new pirenzepine analogue in isolated guinea-pig ileal longitudinal muscle-myenteric plexus.

The new pirenzepine analogue DF 545 has been tested for its muscarinic M1 and M3 receptor antagonist properties in guinea-pig longitudinal muscle-myenteric plexus preparations. McN-A-343-induced inhibition of twitch contractions was taken as a parameter for muscarinic M1 receptor activation while electrical and acetylcholine-induced contractions were considered as a model for muscarinic M3 receptor stimulation. An unexpected contractile effect evoked by McN-A-343 was also investigated. In contrast to pirenzepine, DF 545 only weakly counteracted the M1-mediated McN-A-343 inhibitory effect but blocked M3-related twitch- or acetylcholine-stimulated responses with a 2-fold higher affinity than pirenzepine. Therefore, in this preparation, our findings suggest that DF 545 does not share the selectivity profile exhibited by pirenzepine at ileal muscarinic receptors. Studies on the McN-A-343 contractile effect provide evidence that this agonist may interact with ileal muscarinic effector sites in a different way from other cholinergic agents.

Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.

The mechanism of action of levodropropizine has been investigated in different models of experimentally-induced cough in guinea-pigs. In particular it has been demonstrated that the antitussive drug has a peripheral site of action by injecting the drug intracerebroventricularly (i.c.v.). In these experiments levodropropizine (40 micrograms/50 microliters i.c.v.) did not prevent electrically-induced cough. On the other hand, codeine (5 micrograms/50 microliters i.c.v.) markedly prevented coughing. A difference in the potency ratio of levodropropizine and codeine has been demonstrated in capsaicin-induced cough; after oral administration, codeine was about two to three times more potent than levodropropizine. However, after aerosol administration the two compounds were equipotent. These data might suggest a peripheral site of action for levodropropizine which is related to sensory neuropeptides. Further support for the role of sensory neuropeptides in the mechanism of action of levodropropizine comes from the results obtained in capsaicin-desensitized animals. In this experimental model levodropropizine failed to prevent the vagally elicited cough in neuropeptide-depleted animals, whereas codeine did not differentiate between control and capsaicin-treated animals. In conclusion, our results support the suggestion that levodropropizine has a peripheral site of action. In addition, the interference with the sensory neuropeptide system may explain, at least in part, its activity in experimentally-induced cough.

Gastrointestinal activities of a new pirenzepine-analog, nuvenzepine, in the cat.

Nuvenzepine, a new pirenzepine-analog, administered intraduodenally, displayed a long-lasting and dose-dependent inhibition of neostigmine-induced intestinal motility in anaesthetized cats. On ileal motor activity, the compound showed a potency 10 times greater than that of pirenzepine, and, although to a lesser extent, it was also active, unlike pirenzepine, on colonic stimulated motility. Furthermore, in conscious cats, nuvenzepine inhibited pentagastrin-stimulated gastric acid secretion resulting 25-30 times more potent than pirenzepine. The observed differences between antisecretory and antispastic activities displayed by nuvenzepine and pirenzepine suggest that the new pirenzepine-analog may act on gastrointestinal functions through an additional non-anticholinergic mechanism.

Antihistaminic/antiallergic activity of 2-dialkylaminoalkylthio(oxy)-1-substituted benzimidazoles: evaluation "in vitro" and "in vivo".

A new series of 2-dialkylamino-alkylthio(oxy)-1-substituted benzimidazoles synthesized in our laboratories was found to have promising antihistaminic activity. The results of pharmacological screening ("in vitro": radioreceptor binding and isolated organs; "in vivo": protection against mortality induced by histamine or by compound 48/80, passive cutaneous anaphylaxis, and prolongation of barbiturate-induced sleeping-time) gave clear-cut structure-activity relationships. This series of products has a general selectivity towards H1 receptors, weak antiallergic properties and negligible central effects. DF 10967 (1-ethoxyethyl-2-dimethyl-aminoethylthiobenzimidazole) was the most interesting compound, being very potent both "in vitro" (Ki = 3.2 +/- 0.8 nM) and "in vivo" (ID50 11 micrograms/kg, i.p. and 8 micrograms/kg, i.p. against histamine- and 48/80-induced mortality), with no central effects. The last finding is probably due to poor penetration into the brain (as confirmed by "in vivo" binding test with [3H]-mepyramine) and to lack of interaction with other central receptors.

Effects of two new pirenzepine analogs on the contractile response of the guinea-pig oesophageal muscularis mucosae to acetylcholine, bethanechol, histamine and high potassium.

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.

Comparison of the gastric antisecretory effects of ramixotidine dihydrochloride (CM 57755), a new H2 receptor antagonist, and cimetidine in dogs.

This paper compares the effects of ramixotidine dihydrochloride (CM 57755) with those of cimetidine on gastric acid secretion and gastrin release in conscious dogs chronically fitted with Heidenhain pouches and/or gastric fistulae. At equimolar doses, intravenous (i.v.) or intragastric (i.g.) CM 57755 caused similar inhibition of dimaprit- or pentagastrin-induced secretion than cimetidine. Acid secretion stimulated by a meat meal was significantly reduced by both CM 57755 and cimetidine. Neither CM 57755 (4.5 and 9 mumol/kg) nor cimetidine (4 mumol/kg) modified gastrin release, while cimetidine (8 mumol/kg) significantly increased it. Judging from these results, while CM 57755 appears to be an inhibitor of gastric acid secretion induced by different stimulants in dogs with potency comparable to cimetidine. The increase in plasma gastrin levels seen after cimetidine but not after CM 57755 suggests that cimetidine releases gastrin by a mechanism independent of H2 receptor antagonism.

Inhibition of dimaprit- and pentagastrin-induced gastric acid secretion in cats by the new histamine H2 antagonist, CM 57755.

The antisecretory effects of CM 57755, a new histamine-H2 receptor antagonist, have been compared with those of cimetidine on gastric acid secretion induced by intravenous infusions of dimaprit or pentagastrin into conscious cats with chronically implanted gastric fistulae. Intravenous infusion of CM 57755 induced a parallel shift to the right of the dimaprit dose-response curve. The potency of CM 57755 was comparable with that of cimetidine as shown by similar doses causing a 5-fold displacement to the right of the dimaprit dose-response curve (4.9 mumol kg-1 h-1 for CM 57755 and 4.7 mumol kg-1 h-1 for cimetidine). Unlike that with dimaprit, the acid secretion stimulated by increasing doses of pentagastrin was inhibited by CM 57755 with depression of the maximal effect, indicating non-competitive antagonism. In a second series of experiments the time course of the anti-secretory action of intragastrically administered CM 57755 was studied from the gastric acid secretion induced by constant infusion of dimaprit. At equieffective doses, CM 57755 caused more sustained inhibition than cimetidine.

Pharmacological profile of a new peptidic gastrin antagonist.

Boc-Trp-Met-Asp-NH2 was described as the smallest peptidic fragment which presented gastric antisecretory activity. Some pharmacological aspects of a peptide analogue, Boc-Trp-Leu-Asp-NH2 (Boc-WLD-NH2), were studied on the main biological functions of gastrin. This compound was found to inhibit the binding of gastrin to isolated gastric fundic mucosal cells (IC50 50 microM). On pentagastrin-induced gastric acid secretion in the rat, a dose-dependent inhibition was observed with an ID50 of 55 mumol/kg when pentagastrin (1 microgram/kg per h) was continuously infused and with an ID50 of 7.8 mumol/kg when pentagastrin (1 microgram/kg) was bolus i.v. injected. Similar inhibition was observed on acid secretion induced by pentagastrin in the isolated rat gastric mucosa (IC50 100 microM), whereas the tripeptide had no effect when acid output was triggered by histamine. A dose-dependent inhibition with the tripeptide was shown on pentagastrin induced guinea-pig ileum contractions (IC50 31 microM). The compound had no activity on histamine-stimulated guinea-pig atria (histamine H2-receptor). These results suggest some evidence for a selective antigastrin activity.

In vivo and in vitro effects of CM 57755, a new gastric antisecretory agent acting on histamine H2 receptors.

The pharmacological activity of CM 57755, a new gastric antisecretory compound of the anti-H2 type, was studied in certain in vivo and in vitro preparations. In stomach-lumen perfused rats it proved to be, on a molar basis, half as active as cimetidine and 1/13 as active as ranitidine in inhibiting histamine-induced gastric acid secretion. On the other hand, CM 57755 administered to conscious gastric-fistula cats, either i.v. or intragastrically, depressed the hypersecretory plateau evoked by constant infusion of dimaprit with a potency comparable to that of cimetidine. In this preparation, the inhibition at equieffective doses of antagonists was more sustained for CM 57755 than for cimetidine and ranitidine. Applied to isolated guinea-pig right atria and gastric mucosa, CM 57755 competitively antagonized histamine effects (respective pA2's: 5.4 and 5.9) but was less potent than expected from its in vivo antisecretory activity. Bioavailability and/or biotransformation are the factors most likely to account for the differences observed between species, and between in vivo and in vitro studies for this long-acting antisecretory agent.