Novel histamine H 3 ‐receptor antagonists and partial agonists with a non‐aminergic structure

We determined the affinities of eight novel histamine H 3 ‐receptor ligands (ethers and carbamates) for H 3 ‐receptor binding sites and their agonistic/antagonistic effects in two functional H 3 ‐receptor models. The compounds differ from histamine in that the ethylamine chain is replaced by a propyloxy chain; in the three ethers mentioned below (FUB 335, 373 and 407), R is n ‐pentyl, 3‐methylbutyl and 3,3‐dimethylbutyl, respectively. The compounds monophasically inhibited [ 3 H]‐ N α ‐methylhistamine binding to mouse cerebral cortex membranes (p K i 7.51 – 9.53). The concentration‐response curve of histamine for its inhibitory effect on the electrically evoked [ 3 H]‐noradrenaline overflow from mouse cortex slices was shifted to the right by these compounds (apparent pA 2 6.61 – 8.00). Only FUB 373 and 407 inhibited the evoked overflow by themselves (intrinsic activities 0.3 and 0.4); these effects were counteracted by the H 3 ‐receptor antagonist clobenpropit. [ 35 S]‐GTPγS binding to mouse cortex membranes was stimulated by the H 3 ‐receptor agonist ( R )‐α‐methylhistamine in a manner sensitive to clobenpropit. Among the novel compounds only FUB 373 and 407 stimulated [ 35 S]‐GTPγS binding (intrinsic activities 0.6 and 0.4). In conclusion, the novel compounds are partial H 3 ‐receptor agonists (FUB 373 and 407) or H 3 ‐receptor antagonists; comparison with FUB 335 shows that the transition from antagonist to agonist is caused by a slight structural change. A protonated N atom in the side chain is not necessary for agonism at H 3 receptors, proposing a receptor‐ligand interaction different from that of classical agonists.British Journal of Pharmacology (2001) 132 , 1665–1672; doi: 10.1038/sj.bjp.0704013