POTENCIES OF ANTAGONISTS CHEMICALLY RELATED TO IODOPROXYFAN AT HISTAMINE H-3 RECEPTORS IN MOUSE-BRAIN CORTEX AND GUINEA-PIG ILEUM - EVIDENCE FOR H-3 RECEPTOR HETEROGENEITY

We determined the affinities of 16 newly synthesized H-3 receptor anta gonists in an H-3 receptor binding assay and the potencies of 12 of th ese compounds at functional H-3 receptors in the mouse brain cortex an d guineapig ileum. The compounds differ from histamine in that the C-C -N side chain is replaced by a chain of the structure C-C-C-O. The two major aims of the study were (1) to investigate whether the two funct ional Hg receptors are pharmacologically different and (2) to derive s tructure-activity relationships. The specific binding of H-3-N-alpha-m ethylhistamine to rat brain cortex membranes was monophasically displa ced by each of the 16 compounds at pK(i) values ranging from 7.30 to 9 .48. In superfused mouse brain cortex slices preincubated with H-3-nor adrenaline, the electrically evoked tritium overflow was slightly decr eased by iodoproxyfan and its deiodo analogue; this effect was counter acted by the H-3 receptor antagonist clobenpropit. The other compounds did not affect the evoked tritium overflow by themselves. The concent ration-response curve of histamine for its inhibitory effect on the el ectrically evoked tritium overflow was shifted to the right by the 12 compounds with apparent pA(2) values ranging from 7.02 to 9.00. The 12 compounds also shifted to the right the concentration-response curve of R-alpha-methylhistamine for its inhibitory effect on the electrical ly induced contraction in guinea-pig ileum strips; the apparent pA(2) values ranged from 5.97 to 9.00. Iodoproxyfan decreased the electrical ly induced contraction by itself and this effect was counteracted by t he H-3 receptor antagonist thioperamide. The apparent pA(2) values in the two functional H-3 receptor models showed a highly significant cor relation (r=0.882; P<0.001). Highly significant correlations were also obtained when the pK(i) values of the compounds in the binding assay were compared to their apparent pA(2) values in the mouse brain (r=0.7 99; P<0.004) and in the guinea-pig ileum (r=0.851; P<0.001). In each o f the three experimental models, iodoproxyfan was the most potent comp ound; its deiodo analogue was less potent by more than 1.1 log units. The present results show that the compounds under study possess modera te to high affinity and/or (partial) H-3 receptor antagonist potency. The two functional H-3 receptors in the mouse brain cortex and the gui nea-pig ileum may be slightly different; further studies are necessary to clarify whether this difference is due to H-3 receptor heterogenei ty, species variants or differences in the efficiency of receptor coup ling. The marked difference in the affinity/potency between iodoproxyf an and its deiodo analogue may suggest that a highly lipophilic residu e in that part of the molecule favours a high affinity/antagonistic po tency at H-3 receptors.