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Novel histamine H3 receptor antagonists: affinities in an H3 receptor binding assay and potencies in two functional H3 receptor models

1 We determined the affinities of ten novel H3 receptor antagonists in an H3 receptor binding assay and their potencies in two functional H3 receptor models. The novel compounds differ from histamine in that the aminoethyl side chain is replaced by a propyl or butyl chain linked to a polar group (amide, thioamide, ester, guanidine, guanidine ester or urea) which, in turn, is connected to a hexocyclic ring or to an alicyclic ring containing an alkyl residue. 2 The specific binding of [3H]‐Nα‐methylhistamine to rat brain cortex membranes was monophasically displaced by each of the ten compounds at pKi values ranging from 7.56 to 8.68. 3 Inhibition by histamine of the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]‐noradrenaline was antagonized by the ten compounds and the concentration‐response curve was shifted to the right with apparent pA2 values ranging from 7.07 to 9.20. 4 The electrically induced contraction in guinea‐pig ileum strips (which was abolished by atropine) was inhibited by the H3 receptor agonists R‐(−)‐α‐methylhistamine (pEC50 7.76), Nα‐methylhistamine (7.90) and imetit (8.18). The concentration‐response curve of R‐(−)‐α‐methylhistamine was shifted to the right by thioperamide (apparent pA2 8.79) and by the ten novel compounds (range of pA2 values 6.64–8.81). 5 The affinities and potencies were compared by linear regression analysis. This analysis was extended to thioperamide, the standard H3 receptor antagonist, which is also capable of differentiating between H3A and H3B sites. Comparison of the apparent pA2 values in the two functional H3 receptor models yielded a regression coefficient of 0.77 (P < 0.02). When the pA2 of the drugs in the mouse brain cortex were compared to the pKi for H3 sites (ten novel compounds) and for H3A sites (thioperamide), a significant correlation (r = 0.87; P < 0.001) was obtained. There was, however, no significant correlation when the pKi of thioperamide for H3B sites was used instead (r = 0.52). In a similar manner, comparison of the pA2 in the guinea‐pig ileum with the pKi in the binding assay yielded a significant correlation (r = 0.70, P < 0.05) only when the pKi of thioperamide for H3A sites was used but not when its pKi for H3B sites was considered (r = 0.17, NS). 6 On the basis of these results, structure‐activity relationships for the novel H3 receptor antagonists, and the nature of the H3 receptors in the guinea‐pig ileum and mouse brain, are considered.