To investigate stereospecificity and the mechanism of activation of the histamine H3-receptor, a series of 2-(R and S)-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives were synthesized. In these compounds, the structures of the well-known antagonist iodoproxyfan and the full agonists R- or S-(alpha)-methylhistamine were combined in one molecule. The obtained "hybrid" molecules were tested for H3-receptor affinity on rat cerebral cortex. Some selected compounds were further screened for H3-receptor functional activity with GTPgamma[35S] autoradiography studies using rat brain tissue sections. The affinity of all the synthesized compounds (-log Ki = 5.9-7.9) was lower than that found for iodoproxyfan or two of its analogues; however, the compounds showed stereospecificity. The S-configuration of the series of 2-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives, which resembles the stereochemistry of R-(alpha)-methylhistamine, was more favorable. Incorporation of an amino group in the propyl chain of iodoproxyfan and analogues did not alter the antagonistic behavior for compounds with an aromatic side chain. However, when also the aromatic moiety was replaced by a cyclohexyl group, the compounds behaved as agonists. This indicates that an interaction between the side chain amino group and the H3-receptor protein is involved in H3-receptor activation. The 2-(S)-amino-3-(1H-imidazol-4(5)-yl)propyl cyclohexylmethyl ether (23) has H3-receptor agonistic properties with high affinity for the histamine H3-receptor (-log Ki = 7.9 +/- 0.2) and might serve as a useful tool for further studies concerning drug design and receptor-ligand interactions.

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This study proposes a new mechanism of activation of the histamine H 3 -receptor based on stabilization of the active state of the receptor protein by a proton relay process. A series of histamine H 3 -receptor agonists and one antagonist, all containing an imidazole and a side chain amino group, were studied using 1 H NMR and ab initio quantum mechanical calculations. A significant correlation (r ) -0.87) between the formation energy of the active reaction intermediate and the agonistic activity is found. The calculated proton-transfer energies and pK a values of the reaction intermediates (at the MP2/6-31+G*//HF/6-31+G* level in the gas and aqueous phases), as well as, 1 H NMR conformational analysis, enable a qualitative and quantitative determination of intramolecular hydrogen bonding and its effect on proton release from the imidazole N(τ)-atom. The results indicate that the histamine H 3 -receptor is not activated by a proton release from imidazole N(τ)-atom but through adoption of a folded conformation of the ligand which stabilizes the active state of the receptor by an intramolecular hydrogen bond.

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(Cyclohexylmethyloxymethyl)(1H-imidazol-4-iomethyl)-(S)-ammonium dichloride, C(13)H(25)N(3)O(+).2Cl(-), and (4-bromobenzyl)(1H-imidazol-4-iomethyl)-(S)-ammonium dichloride, C(13)H(18)BrN(3)O(+).2Cl(-), are model compounds with different biological activities for evaluation of the histamine H3-receptor activation mechanism. Both title compounds occur in almost similar extended conformations.