NOVEL HISTAMINE-H-3 RECEPTOR ANTAGONISTS - AFFINITIES IN AN H-3 RECEPTOR-BINDING ASSAY AND POTENCIES IN 2 FUNCTIONAL H-3 RECEPTOR MODELS

1 We determined the affinities of ten novel H-3 receptor antagonists in an H-3 receptor binding assay and their potencies in two functional H-3 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 [H-3]-N-alpha-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the ten compounds at pK(i) 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 [H-3]-noradrenaline was antagonized by the ten compounds and the concentration-response curve was shifted to the right with apparent pA(2) 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 H-3 receptor agonists R-(-)-alpha-methylhistamine (pEC(50), 7.76), N-alpha-methylhistamine (7.90) and imetit (8.18). The concentration-response curve of R-(-)-alpha-methylhistamine was shifted to the right by thioperamide (apparent pA(2) 8.79) and by the ten novel compounds (range of pA(2) values 6.64-8.81). 5 The affinities and potencies were compared by linear regression analysis. This analysis was extended to thioperamide, the standard H-3 receptor antagonist, which is also capable of differentiating between H-3A and H-3B sites. Comparison of the apparent pA(2) values in the two functional H-3 receptor models yielded a regression coefficient of 0.77 (P < 0.02). When the pA(2) of the drugs in the mouse brain cortex were compared to the pK(i) for H-3 sites (ten novel compounds) and for H-3A sites (thioperamide), a significant correlation (r = 0.87; P < 0.001) was obtained. There was, however, no significant correlation when the pK(i) of thioperamide for H-3B sites was used instead (r = 0.52). In a similar manner, comparison of the pA(2) in the guinea-pig ileum with the pK(i) in the binding assay yielded a significant correlation (r = 0.70, P < 0.05) only when the pK(i) of thioperamide for H-3A sites was used but not when its pK(i) for H-3B sites was considered (r = 0.17, NS). 6 On the basis of these results, structure-activity relationships for the novel H-3 receptor antagonists, and the nature of the H-3 receptors in the guinea-pig ileum and mouse brain are considered.