piperidines and lamtidine

New anti-Helicobacter pylori (H. pylori) agents endowed with H2-antagonists properties were obtained by combining the lamtidine derived pharmacophoric group with the antibiotic calvatic acid. All the compounds were tested for their irreversible H2-antagonist properties and for their ability to inhibit 20 H. pylori strains, two of them metronidazole resistant. The most active derivative (compound 4) displayed antimicrobial activity similar to metronidazole.

Topics: Animals; Anti-Bacterial Agents; Benzoates; Binding, Competitive; Combinatorial Chemistry Techniques; Dose-Response Relationship, Drug; Drug Resistance; Guinea Pigs; Heart Atria; Helicobacter pylori; Histamine; Histamine H2 Antagonists; Metronidazole; Microbial Sensitivity Tests; Nitriles; Piperidines; Receptors, Histamine H2; Structure-Activity Relationship; Triazoles

The histamine H2 receptor-blocking activity of ranitidine and lamtidine analogues has been investigated to gain information on the structure of the receptor area adjacent to the site fitted by the polar group. The introduction of differently shaped alkyl moieties on the polar group is always accompanied by maintenance or by an increase of H2 receptor antagonism with respect to the starting lead compound (KB on guinea-pig isolated atria ranging from 49 nM to 1.5 nM). The results seem to indicate the presence in the histamine H2 receptor of an area of a predominantly hydrophobic nature located at the boundary of the site fitted by the polar group.

Topics: Animals; Binding Sites; Cerebral Cortex; Cimetidine; Guinea Pigs; Heart Atria; Histamine H2 Antagonists; Ileum; Male; Piperidines; Ranitidine; Receptors, Histamine H2; Structure-Activity Relationship; Triazoles

Topics: Amides; Chromatography, Gas; Histamine H2 Antagonists; Piperidines; Stereoisomerism; Terpenes; Triazoles

New compounds structurally related to cimetidine, ranitidine and lamtidine have been prepared and tested for their histamine H2-receptor blocking activity on guinea-pig atria, rat perfused stomach and frog isolated gastric mucosa. These derivatives contain as a polar group, a diaminofurazan moiety, a 3-amino-4-methylfurazan or a 3-amino-4-phenylfurazan moiety. Ranitidine and lamtidine analogues display strong H2-antagonist activity in-vitro (KB on atria 0.037 microM and 0.0039 microM, respectively) and in-vivo on the lumen-perfused stomach of the anaesthetized rat (ID50 0.13 mumol kg-1 and 0.023 mumol kg-1 i.v., respectively). However, lamtidine analogues are ineffective in blocking the histamine-induced increase of H+ output in the frog isolated gastric mucosa. On the basis of the anomalous results in the frog, it is concluded that caution must be exercised in extrapolating information from amphibian to mammalian tissues with regard to the structure and the function of histamine receptors.

Topics: Animals; Cimetidine; Gastric Mucosa; Guinea Pigs; In Vitro Techniques; Male; Piperidines; Rana temporaria; Ranitidine; Rats; Receptors, Histamine H2; Stomach; Triazoles

The possibility that the aromatic component in the classical H2-antagonists might not be essential for histamine H2-receptor blockade has been investigated. In the ranitidine series the removal of the furan ring is accompanied by a drastic decrease in H2-blocking activity, but not by its disappearance (compound HB5:KB on guinea pig isolated atria 31.6 microM) whereas in the lamtidine analogues the substitution of the phenyl moiety with the more reduced pi-bonded CH3-C = N-area generates a compound whose activity is comparable to that of cimetidine (KB on atria 1.12 microM; ID50 in the lumen-perfused stomach of the anaesthetized rat 3.61 mumol/kg i.v.). The results also indicate that the diaminofurazan group confers high affinity at the histamine H2-receptor. It is concluded that the aromatic portion of H2-antagonists related to ranitidine and lamtidine is not a minimal requisite for activity when an appropriate polar group is used as an "urea equivalent" moiety.

Topics: Animals; Chemical Phenomena; Chemistry; Gastric Acid; Gastric Mucosa; Guinea Pigs; Heart Rate; Histamine H2 Antagonists; Ileum; Piperidines; Rana temporaria; Ranitidine; Rats; Structure-Activity Relationship; Triazoles

The antisecretory potency and duration of action of the new histamine H2-receptor antagonist AH 22216 have been compared with those of cimetidine, ranitidine and SK & F 93479 against histamine-induced gastric acid secretion in the conscious Heidenhain pouch dog. Ranitidine was 4-6 times more potent than cimetidine, with a similar duration of action. SK & F 93479 was approximately twice as potent as ranitidine and had a slightly longer duration of action. AH 22216 was most potent of the four H2-antagonists, some 20-30 times more active than cimetidine, and had an extremely prolonged duration of action.

Topics: Animals; Cimetidine; Dogs; Furans; Gastric Acid; Guanidines; Histamine H2 Antagonists; Male; Piperidines; Pyrimidinones; Ranitidine; Time Factors; Triazoles

We compared the interaction of AH 22216 (a new histamine H2 receptor antagonist) and cimetidine on the receptor-cAMP systems sensitive to histamine and to Vasoactive Intestinal Peptide (VIP) in the human gastric cancer cell line HGT-1. When added simultaneously with histamine (10(-4) M), the potency of AH 22216 is similar to that of cimetidine (IC50 = 4-6.6 X 10(-6) M, respectively). Schild plot analysis indicated a non-competitive inhibition by AH 22216 (pA2 = 6.22, slope = 1.4 +/- 0.03). Preincubations of AH 22216 (10 min, 10(-5) M) with HGT-1 cells (even after a washout period) resulted in a complete and persistent (60 min) inactivation of the subsequent histamine effect, without changing the kinetics of the VIP-induced stimulation in the system. Under these conditions, the potency of AH 22216 increased from 6.6 to 0.7 X 10(-6) M. This inactivation was not observed with cimetidine. The data indicate that AH 22216 is an irreversible and specific inhibitor of the gastric histamine H2 receptor.

Topics: Cell Line; Cells, Cultured; Cyclic AMP; Dose-Response Relationship, Drug; Histamine; Humans; Piperidines; Receptors, Histamine; Receptors, Histamine H2; Stomach; Triazoles; Vasoactive Intestinal Peptide

AH 22216 is a new histamine-H2-receptor antagonist which possesses a triazole ring. When compared to cimetidine, AH 22216 is about 100 times more potent (Ki = 0.21 x 10(-8) M) in inhibiting histamine-stimulated acid secretion in isolated rabbit gastric cells. These two antihistamines have no effect on carbachol-stimulated acid secretion in the system. The data indicate that AH 22216 interacts directly and specifically on the gastric H2-receptor of the parietal cell and are consistent with the reported pharmacological potencies of AH 22216 and cimetidine on histamine-induced gastric-acid secretion in vivo. AH 22216 could thus be a useful therapeutic agent in patients with peptic ulcers.

Topics: Aminopyrine; Animals; Cimetidine; Gastric Acid; Gastric Mucosa; Histamine; Male; Piperidines; Rabbits; Receptors, Histamine; Receptors, Histamine H2; Triazoles