Relation between pharmacological response and receptor binding with histamine blocking drugs. Irreversible antagonism of three analogues of mifentidine on right atrium and cerebral cortex of the guinea-pig

Abstract

The effects of the H2-receptor antagonists cimetidine, ranitidine, mifentidine and three analogues of mifentidine, were studied on the spontaneously beating right atrium (H2-antagonism) and membranes of the cerebral cortex (displacement of 3H-tiotidine), both obtained from the male guinea-pig. The choice of these compounds was based on preliminary experiments in which some mifentidine analogues were shown to displace tiotidine from the H2-receptor in a deviant manner. In the present study we investigated the relation between pharmacological response and receptor binding, also testing the degree of irreversible antagonism of these compounds in the atrium (functional) and cerebral cortex (binding) model. Our data indicate that a relation between the two different approaches for measuring the effect on the H2-receptor can be found, although some differences emerged as well.

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

“…A different number of spare receptors could also explain why APT and I-APT did not produce insurmountable antagonism in the right atrium (Hirschfeld et al, 1992); in this tissue, in fact, a receptor reserve of approximately 97% at maximal histamine responses has been calculated (Kramer et al, 1987).…”

“…The more pronounced rightward shift of the CRC to histamine observed in the papillary muscle in comparison with rat gastric fundus could be related to a larger receptor reserve for histamine H2 receptors in the heart, so that APT and I-APT, although reducing agonist-receptor occupancy will not produce a depression of the maximal response. A different number of spare receptors could also explain why APT and I-APT did not produce insurmountable antagonism in the right atrium (Hirschfeld et al, 1992); in this tissue, in fact, a receptor reserve of approximately 97% at maximal histamine responses has been calculated (Kramer et al, 1987).…”

Irreversible H2-antagonism of the four isomeric butyl analogues of mifentidine

“…The ratio E,E: E,Z is governed by the substituent R. The ratios E,E/E,Z were determined by NMR studies on the amidinimn cations (data not shown). Previously, we reported [1] receptor [3H]tiotidine displacement binding studies with some mifentidine analogues which instead of isopropyl contain higher alkyl-groups (as in mifentidine). The results indicated that these compounds bind irreversibly to sites different from tiotidine binding loci but allosterically influencing the interaction of tiotidine with the H2-receptor , causing pseudo-irreversible H2-antagonism by some kind of site-site interaction between the binding loci for the tested compounds and for histamine, leading to negative cooperativity.…”