Meta-Substituted Aryl(thio)ethers as Potent Partial Agonists (or Antagonists) for the Histamine H3 Receptor Lacking a Nitrogen Atom in the Side Chain

4-(3-Aryloxypropyl)-1H-imidazoles, which possess a meta-positioned substituent in the aryl ring, have been synthesized and tested for activity at histamine H3 receptors. The compounds having a CN, Me, or Br substituent were found to be antagonists, whereas CF3, Et, i-Pr, t-Bu, COCH3, or NO2 substituents remarkably afforded partial agonists when tested in vitro on rat cerebral cortex synaptosomes for inhibition of [3H]histamine release. The compounds were also active in vivo, and furthermore, the CF3-substituted compound trifluproxim (UCL 1470, 7) acted as a potent full agonist in vivo, having ED50 = 0.6 ± 0.3 mg/kg per os in mice for inhibition of brain N τ-methylhistamine formation. Related structures have also been investigated; homologues 4-[4-(3-(trifluoromethyl)phenoxy)butyl]-1H-imidazole and 4-[2-(3-(trifluoromethyl)phenylthio)ethyl]-1H-imidazole are shown to be partial agonists, whereas the O isostere 4-[2-(3-(trifluoromethyl)phenoxy)ethyl]-1H-imidazole is an antagonist as is the S homologue 4-[3-(3-(trifluoromethyl)phenylthio)propyl]-1H-imidazole and its CH2 isostere 4-[4-(3-(trifluoromethyl)phenyl)butyl]-1H-imidazole.