| Abstract
| - 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 fullagonists R- or S-(α)-methylhistamine were combined in one molecule. The obtained “hybrid”molecules were tested for H3-receptor affinity on rat cerebral cortex. Some selected compoundswere further screened for H3-receptor functional activity with GTPγ[35S] autoradiographystudies 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, thecompounds 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-(α)-methylhistamine, was more favorable. Incorporation of an amino group in the propyl chain ofiodoproxyfan and analogues did not alter the antagonistic behavior for compounds with anaromatic side chain. However, when also the aromatic moiety was replaced by a cyclohexylgroup, the compounds behaved as agonists. This indicates that an interaction between theside chain amino group and the H3-receptor protein is involved in H3-receptor activation. The2-(S)-amino-3-(1H-imidazol-4(5)-yl)propyl cyclohexylmethyl ether (23) has H3-receptor agonisticproperties with high affinity for the histamine H3-receptor (−log Ki = 7.9 ± 0.2) and mightserve as a useful tool for further studies concerning drug design and receptor−ligandinteractions.
|
