Novel histamine H3-receptor antagonists and partial agonists with a non-aminergic structure

Abstract

1. We determined the affinities of eight novel histamine H3-receptor ligands (ethers and carbamates) for H3-receptor binding sites and their agonistic/antagonistic effects in two functional H3-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. 2. The compounds monophasically inhibited [3H]-Nα-methylhistamine binding to mouse cerebral cortex membranes (pKi 7.51-9.53). 3. The concentration-response curve of histamine for its inhibitory effect on the electrically evoked [3H]-noradrenaline overflow from mouse cortex slices was shifted to the right by these compounds (apparent pA2 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 H3-receptor antagonist clobenpropit. 4. [35S]-GTPγS binding to mouse cortex membranes was stimulated by the H3-receptor agonist (R)α-methylhistamine in a manner sensitive to clobenpropit. Among the novel compounds only FUB 373 and 407 stimulated [35S]-GTPγS binding (intrinsic activities 0.6 and 0.4). 5. In conclusion, the novel compounds are partial H3-receptor agonists (FUB 373 and 407) or H3-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 H3 receptors, proposing a receptor-ligand interaction different from that of classical agonists.