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

Abstract

1 We determined the a nities of eight novel histamine H 3 -receptor ligands (ethers and carbamates) for H 3 -receptor binding sites and their agonistic/antagonistic e ects in two functional H 3 -receptor models. The compounds di er 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 [ 3 H]-N a -methylhistamine binding to mouse cerebral cortex membranes (pK i 7.51 ± 9.53). 3 The concentration-response curve of histamine for its inhibitory e ect on the electrically evoked [ 3 H]-noradrenaline over¯ow 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 over¯ow by themselves (intrinsic activities 0.3 and 0.4); these e ects were counteracted by the H 3 -receptor antagonist clobenpropit. 4 [ 35 S]-GTPgS binding to mouse cortex membranes was stimulated by the H 3 -receptor agonist (R)-a-methylhistamine in a manner sensitive to clobenpropit. Among the novel compounds only FUB 373 and 407 stimulated [ 35 S]-GTPgS binding (intrinsic activities 0.6 and 0.4). 5 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 di erent from that of classical agonists.

Model structures of α-2 adrenoceptors in complex with automatically docked antagonist ligands raise the possibility of interactions dissimilar from agonist ligands

“…This alternative recognition mechanism agrees with the available experimental data and requires fewer structural deviations with regard to the only known structure of a GPCR, bovine rhodopsin. Similar binding modes have been observed in X-ray structures of proteins-ligand complexes unrelated to GPCRs, and may also occur in proteins that process catecholamines (Madras et al, 2003;McMillan et al, 2004) and in other GPCRs that have D3.32 but bind non-aminergic ligands (Nickel et al, 2001;Roth et al, 2002).…”

“…Alternatively, if we were to enforce an ion-pair, then substantial changes in the main-chain conformation would be necessary that are not reXected in the existing structural data. Interestingly, for some other GPCRs having D3.32, non-nitrogenous and non-aminergic ligands are known, e.g., for the opioid and histaminergic H3 receptors (Nickel et al, 2001;Roth et al, 2002). We have so far not been able to identify any commercially available non-nitrogenous antagonist ligands that bind to an adrenergic receptor.…”

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

“…In simulations of antagonist/hH 3 R complexes the conformational switch of F5.47 towards the inside of the binding pocket was inhibited due to the presence of the ligand. If one assumes a role of F5.47 in activation, the transition from partial agonism to inverse agonism caused by slight structural changes, as for example observed in the series FUB373, FUB335, FUB407 and FUB397 [49] could be correlated to the conformational changes of F5.47. Antagonists FUB335 and FUB397 would thus block the conformational switch of F5.47 due to the structurally more demanding imidazole side chain.…”

Histamine H3 Receptor Antagonists Go to Clinics

“…to mice (ED 50 ϭ0.3; i.a.ϭ1). 109,110) Although actually imidazole-containing antagonists have less therapeutic relevance than non-imidazoles new structures are designed in order to use them as pharmacological tools, i.e. in the differentiation of the histamine receptor subtypes or clarification of molecular aspects.…”