Histamine H2-binding on guinea pig cerebral cortex

Abstract

The Kd-values of some histamine H2-active compounds, obtained from radio-ligand-binding studies on a homogenate of the guinea-pig cerebral cortex with 3H-tiotidine as the labelled H2-ligand, were compared with the pA2/pD2-value of these compounds on the guinea-pig right atrium and guinea-pig isolated gastric fundus. A good correlation was found between the pKd of the H2-antagonists and their pA2 on the guinea-pig right atrium. A much poorer correlation however was obtained between the pKd of the agonists on the cerebral cortex and their pD2-values on the guinea-pig right atrium and the gastric fundus. This poor correlation between true affinity and H2-activity of the agonists might be explained by spare receptors as a much better correlation was obtained between pKd and pD2 of partial agonists.

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

“…3 a-f). It has been reported that histamine has a very high efficacy in stimulating the H2-receptor in guinea-pig atrium and therefore gives rise to a large number of spare receptors [11]. The results outlined in Fig.…”

“…Recently Sterk et al [11] reported a good correlation between the true affinity (pKd) of the antagonists cimetidine, ranitidine and mifentidine on the guinea-pig cerebral cortex and their pA2-values on the guinea-pig fight atrium: r=0.99. This indicates that the H2-receptors of these two tissues are similar.…”

“…Different groups characterize the H2-receptor by binding studies using pH]-cimetidine [4][5][6][7], [~H]-ranitidine [8], [3H]-histamine [9] and [3H]-metiamide [10]. In our own laboratory we use [3H]-tiotidine [11], a more potent H2-antagonist than either cimetidine or ranitidine [12]. During the last few years, this H2-subclass of histamine receptors has been characterized by receptor binding studies [4][5][6][7][8][9][10][11].…”

“…In our own laboratory we use [3H]-tiotidine [11], a more potent H2-antagonist than either cimetidine or ranitidine [12]. During the last few years, this H2-subclass of histamine receptors has been characterized by receptor binding studies [4][5][6][7][8][9][10][11]. The question whether a relation between the results obtained from the classical pharmacological studies and the receptor binding studies exists, has not yet been fully elucidated.…”

Structure-Activity Relationships of Histamine H2 Receptor Ligands+

“…This partial structure shows a lower degree of stereoselectivity than the imidazolylpropyl portion [44], which is conferring efficacy and may be varied or replaced over a wide range, resulting in H 2 R agonists with similar or even higher potency than the parent compound. The structural analogues of impromidine described in the literature include, for example, chiral compounds with branched cimetidine-like or homohistamine partial structures [44,45] or substances characterised by other substructures from H 2 R antagonists like thiazoles and furans derived from tiotidine, nizatidine and ranitidine [46,47]. Completely different structures replacing the 5-methylimidazole group are present in the case of hybrid molecules combining the imidazolylpropylguanidine moiety with, for example, arylalkyl [48][49][50][51][52][53][54][55][56], diarylalkyl originating from H 1 R antagonists [57][58][59][60][61], dihydropyridine from calcium channel blockers [62,63] and benzoylimidazolone groups [64] from phosphodiesterase inhibitors (for reviews see [15,65,66]).…”