Abstract
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 μM) whereas in the lamtidine analogues the substitution of the phenyl moiety with the more reduced π-bonded CH3-C=N-area generates a compound whose activity is comparable to that of cimetidine (KB on atria 1.12μM; ID50 in the lumen-perfused stomach of the anaesthetized rat 3.61 μmol/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.
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M. Orsetti and G. Sorba,Harmacological profile of new histamine H 2-receptor antagonists related to cimetidine, ranitidine and lamtidine. J. Pharm. Pharmacol.40, 31–34 (1988).
G. Sorba, R. Calvino, A. Defilippi, A. Gasco and M. Orsetti,Potential histamine H 2-receptor antagonists: diaminofurazan, a new “urea equivalent” group. Eur. J. Med. Chem.20, 571–574 (1985).
A. Defilippi, G. Sorba, R. Calvino, A. Garrone, A. Gasco and M. Orsetti,Potential histamine H 2-receptor antagonists: analogues of classical antagonists containing 4-substituted-3-aminofurazan moieties. Arch. Pharm.321, 77–80 (1988).
G. Sorba, A. Garrone, A. Serafino, A. Gasco and M. Orsetti,Potential histamine H 2-receptor antagonists: ranitidine analogues containing 2-amino-5(6)-substituted-benzimidazole moieties. Eur. J. Med. Chem.21, 391–395 (1986).
M. Orsetti and L. Oggero,New ranitidine analogues containing the 2-aminobenzimidazole moiety: in vivo and in vitro histamine H 2-receptor blocking activity. Agents and Actions24, 109–113 (1988).
G. Sorba, R. Fruttero, A. Gasco and M. Orsetti,Acyclic analogs of classical H 2-antagonists: synthesis and activity of dialkylaminoalkyl substituted ethers and oximes. Eur. J. Med. Chem.22, 255–259 (1987).
J. W. Black, W. A. M. Duncan, C. J. Durant, C. R. Ganellin, and E. H. Parsons,Definition and antagonism of histamine H 2-receptors. Nature236, 385–390 (1972).
G. W. Snedecor and W. G. Cochran,Statistical methods. Iowa State University Press, Ames (1971).
M. S. Ghosh and H. O. Schild,Continuous recording of acid gastric secretion in the rat. Br. J. Pharmacol. Chemother.13, 54–61 (1958).
M. Orsetti, L. Oggero and G. Sorba,Effect of ranitidine on histamine-stimulated acid secretion of the frog gastric mucosa. Riv. It. Farmacol. Ter.15, 7–10 (1984).
R. P. Durbin and E. Heinz,Electromotive chloride transport and gastric acid secretion in the frog. J. Gen. Physiol.41, 1035–1047 (1958).
O. Arunlakshana and H. O. Schild,Some quantitative uses of drug antagonism. Br. J. Pharmacol. Chemother.14, 48–58 (1959).
R. T. Brittain, M. J. Daly, M. J. Humphray and R. Stables,AH22216, a new long acting histamine H 2 receptor antagonist. Br. J. Pharmacol.76, 195P (1982).
A. A. Algieri, G. M. Luke, R. T. Standridge, M. Brown, R. A. Partyka and R. R. Crenshaw,1,2,5-thiadiazole 1-oxide and 1,1-dioxide derivatives. A new class of potent histamine H 2-receptor antagonists. J. Med. Chem.25, 210–212 (1982).
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Orsetti, M. Histamine H2-receptor blocking activity of ranitidine and lamtidine analogues containing aminomethyl-substituted aliphatic systems. Agents and Actions 25, 291–295 (1988). https://doi.org/10.1007/BF01965034
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DOI: https://doi.org/10.1007/BF01965034