Synthesis and in vitro pharmacology of a series of new chiral histamine H3-receptor ligands:: 2-(R and S)-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives

To investigate stereospecificity and the mechanism of activation of the histamine H-3-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)-methylkistamine were combined in one molecule. The obtained "hybrid" molecules were tested for H-3-receptor affinity on rat cerebral cortex. Some selected compounds were further screened for H-3-receptor functional activity with GTP gamma[S-35] autoradiography studies using rat brain tissue sections. The affinity of all the synthesized compounds (-log K-i = 5.9-7.9) was lower than that found for iodoprpxyfan 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 H-3-receptor protein is involved in H-3-receptor activation. The 2-(S)-amino-3-(1H-imidazol-4(5)-yl)propy cyclohexylmethyl ether (23) has H-3-receptor agonistic properties with high affinity for the histamine H-3-receptor (-log K-i = 7.9 +/- 0.2) and might serve as a useful tool for further studies concerning drug design and receptor-ligand interactions.