Meta-substituted aryl(thio)ethers as potent partial agonists (or antagonists) for the histamine H3 receptor lacking a nitrogen atom in the side chain.

Nadia Pelloux-Léon, Abdellatif Fkyerat, Antonia Piripitsi, Wasyl Tertiuk, Walter Schunack, Holger Stark, Monique Garbarg, Xavier Ligneau, Jean-Michel Arrang, Jean-Charles Schwartz, C Robin Ganellin

Index: J. Med. Chem. 47(12) , 3264-74, (2004)

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Abstract

4-(3-Aryloxypropyl)-1H-imidazoles, which possess a meta-positioned substituent in the aryl ring, have been synthesized and tested for activity at histamine H(3) receptors. The compounds having a CN, Me, or Br substituent were found to be antagonists, whereas CF(3), Et, i-Pr, t-Bu, COCH(3), or NO(2) substituents remarkably afforded partial agonists when tested in vitro on rat cerebral cortex synaptosomes for inhibition of [(3)H]histamine release. The compounds were also active in vivo, and furthermore, the CF(3)-substituted compound trifluproxim (UCL 1470, 7) acted as a potent full agonist in vivo, having ED(50) = 0.6 +/- 0.3 mg/kg per os in mice for inhibition of brain N(tau)-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 CH(2) isostere 4-[4-(3-(trifluoromethyl)phenyl)butyl]-1H-imidazole.