CARDIAC AND GASTRIC EFFECTS OF HISTAMINE H-2-RECEPTOR ANTAGONISTS - NO EVIDENCE FOR A CORRELATION BETWEEN LIPOPHILICITY AND RECEPTOR AFFINITY

1 A series of histamine H-2 receptor antagonists with different lipoph ilicity were tested in cardiac and gastric assays in order to reveal p ossible differences in receptor affinity. Lipophilicity of the compoun ds was expressed as CLOG P (theoretically-determined logarithm of octa nol:water partition coefficient) and log k' (logarithm of capacity fac tor, experimentally-determined by reverse-phase high performance liqui d chromatography). 2 Aminopotentidine (APT) and iodoaminopotentidine ( I-APT), which are both lipophilic compounds, behaved as insurmountable antagonists of histamine responses in rat isolated gastric fundus (pK (B) = 6.20+/-0.16 and 6.89+/-0.19, respectively) and guinea-pig isolat ed papillary muscle (pK(B) = 6.34+/-0.37 and 6.81+/-0.26, respectively ). They were approximately as effective as ranitidine (RAN) in reducin g histamine-induced acid secretion in the anaesthetized rat, ID50 valu es being 0.018+/-0.02, 0.020+/-0.03 and 0.036+/-0.01 mu mol kg(-1) i.v . for APT, I-APT and RAN, respectively. Both APT and I-APT had a signi ficantly longer duration of action than RAN. 3 The hydrophilic compoun d, SK&F 92857, was inactive up to 10 mu M in modifying histamine-induc ed acid secretion in the isolated rat stomach. In the papillary muscle , low concentrations (0.1-1 mu M) of this compound produced a competit ive antagonism of the histamine responses (pA(2) value=7.38+/-0.11), w hile a higher concentration (10 mu M) significantly reduced the maxima l response to histamine. 4 RAN competitively antagonized histamine eff ects with a comparable affinity in cardiac and gastric preparations (p A(2) values were 6.42+/-0.09 and 6.78+/-0.38 in heart and stomach, res pectively). 5 Results obtained in this study clearly showed that the d iscrepancies between gastric and cardiac effects observed for some H-2 antagonists are not explained solely by differences in lipophilicity of compounds. Moreover, the significant correlation found between CLOG P and log k' parameter, which takes into account, besides their lipop hilicity, the ionization of the molecules, suggests that ionization ha s a similar influence for all the molecules on the partition between t he lipophilic and aqueous phase.