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 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.
Pelloux-Léon
Nadia
N
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, England, UK.
Fkyerat
Abdellatif
A
Piripitsi
Antonia
A
Tertiuk
Wasyl
W
Schunack
Walter
W
Stark
Holger
H
Garbarg
Monique
M
Ligneau
Xavier
X
Arrang
Jean-Michel
JM
Schwartz
Jean-Charles
JC
Ganellin
C Robin
CR
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D004987:Ethers; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D018100:Receptors, Histamine H3; D013440:Sulfides; C020404:tele-methylhistamine