Cardiac and gastric effects of histamine H₂ receptor antagonists: no evidence for a correlation between lipophilicity and receptor affinity

Abstract

1 A series of histamine H2 receptor antagonists with different lipophilicity were tested in cardiac and gastric assays in order to reveal possible differences in receptor affinity. Lipophilicity of the compounds was expressed as CLOG P (theoretically-determined logarithm of octanol:water partition coefficient) and log k' (logarithm of capacity factor, experimentally-determined by reverse-phase high performance liquid 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 (pKB=6.20+0.16 and 6.89+0.19, respectively) and guinea-pig isolated papillary muscle (pKB= 6.34 + 0.37 and 6.81 + 0.26, respectively). They were approximately as effective as ranitidine (RAN) in reducing histamine-induced acid secretion in the anaesthetized rat, ID50 values being 0.018+0.02, 0.020+0.03 and 0.036+0.01 ymol kg-' i.v. for APT, I-APT and RAN, respectively. Both APT and I-APT had a significantly longer duration of action than RAN. 3 The hydrophilic compound, SK&F 92857, was inactive up to 10 gM in modifying histamine-induced acid secretion in the isolated rat stomach. In the papillary muscle, low concentrations (0.1-1 jIM) of this compound produced a competitive antagonism of the histamine responses (pA2 value = 7.38 + 0.11), while a higher concentration (10 gM) significantly reduced the maximal response to histamine.4 RAN competitively antagonized histamine effects with a comparable affinity in cardiac and gastric preparations (pA2 values were 6.42+0.09 and 6.78+0.38 in heart and stomach, respectively). 5 Results obtained in this study clearly showed that the discrepancies between gastric and cardiac effects observed for some H2 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 lipophilicity, the ionization of the molecules, suggests that ionization has a similar influence for all the molecules on the partition between the lipophilic and aqueous phase.

Removal of digoxin by column for specific adsorption of β2‐microglobulin: A potential use for digoxin intoxication

“…23 On the other hand, ranitidine is a hydrophilic drug and its log (octanol/water partition coefficient for ranitidine) is 0.27. 24 This hypothesis is supported by the in vitro findings of this study that digoxin, but not ranitidine, is well adsorbed by the column.…”

New insights in insurmountable antagonism

“…First, when preincubations are performed with a mixture of surmountable and insurmountable antagonists, each type of antagonist can counteract the effect of the other in a dose‐dependent fashion. This ability of surmountable agonists to attenuate/alleviate insurmountable inhibition has been well documented for 5‐HT 2 and AT 1 ‐receptors [12–14] and was also noticed for NK 2 tachykinin [15], α 2 ‐adrenergic [16], H 2 histamine [17] and bradykinin B 2 receptors [18]. Moreover, many insurmountable antagonists exhibit intermediary properties with only a partial depression of the maximal response along with a rightward shift of the dose–response curve ().…”

Structural requirements for roxatidine in the stimulant effect of rat gastric mucin synthesis and the participation of nitric oxide in this mechanism

“…This radiolabel has successfully been used for the labelling of human H 2 receptors in brain tissue (Traiffort et al , 1992). Aminopotentidine (APT) and iodoaminopotentidine (I‐APT) have been shown to behave as insurmountable antagonists of histamine responses in reducing histamine‐induced acid secretion in the anaesthetized rat (Coruzzi et al , 1996). Results obtained in the present study showed that all compounds except analogue F, displaced the specific [ 125 I]‐APT binding to histamine H 2 ‐receptor sites.…”