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Antagonist affinity measurements at the histamine H2 receptor are independent of the agonist used Antagonist affinity measurements at a given receptor are generally considered to be constant for a given receptor-ligand interaction. However studies of the Gs-coupled human β2-adrenoceptor have shown that antagonist affinity measurements can vary up to 10-fold in CRE-gene transcription assays depending on the efficacy of the competing agonist (Baker et al., 2003). Antagonist affinity measurements at the human β1 and β3-adrenoceptors also vary depending on the competing agonist and this has been attributed to the presence of at least two active sites of the receptor (Granneman 2001; Baker 2005). The aim of this study was to determine whether the antagonist affinity measurements at another Gs-coupled receptor, the human histamine H2-receptor, change with the nature of the competing agonist used. CHO cells stably expressing the human histamine H2-receptor and a cAMP response element (CRE)-secreted placental alkaline phosphatase (SPAP) reporter gene were used. CRE-SPAP production was measured as previously described (Baker et al., 2003). The affinities of seven H2-antagonists were determined in functional CRE-SPAP assays from parallel shifts of agonist concentration response curves in a similar manner to that described in Baker et al., 2003. Histamine, Nα-methylhistamine (NαMH) and amthamine were found to be full agonists in this system. Dimaprit, however, has been reported to be a lower efficacy H2-receptor agonist (Hill, 1990). In the present study, maximum responses to dimaprit decreased with increasing concentrations of the longer acting antagonist ICI 162846 confirming this lower efficacy. Unlike the β2-adrenoceptor, antagonist affinities measurements at the H2 receptor appear the same regardless of the efficacy of the competing ligands (Table 1).
Table1. Log K D values of several antagonists at the human H2 receptor (mean ± s.e.m.)
Baker J.G. et al., (2003). Mol. Pharmacol. 64, 679-688. |
