Structure - activity studies with histamine H3 - receptor ligands

Ganellin,C.R., Fkyerat, A., Hosseini, S.K., Khalaf,Y. S:, Piripitsi, A., Tertiuk, W., Arrang, J.M. (*), Garbarg,M.(*), Ligneau, X.(**) and Schwartz, J.C.(*)

Department of Chemistry, Christopher Ingold Laboratories. University College London. England.
(*) Unité 109 de Neurobiologie et Pharmacologie. Centre Paul Broca de l'INSERM. Paris
(**)Supported by Laboratoire Bioprojet, 30 rue des Francs- Bourgeois,75003.Paris

Ars Pharm.36;(3);455-468, (1995)


Key words: Histamine, Aryloxyalquyl-imidazoles, H3-agonists, H3-antagonists,

Abstract

Analogues of thioperamide have been systhesised and tested in vitro on rat cerebral cortex to explore structure-activity relatioships with the intention of designing compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Compounds derived from histamine and having an aromatic nitrogen- containing heterocycle on the side-chain amino group have been found to act as H3- antagonists. These have served as leads to provide aryloxyethyl - and aryloxypropylimidazoles which are potent H3 antagonists of histamine.
Structure-activity relation ships for agonists are briefly reviewed. Analogues of the very potent and selective agonist, imetit (S-[2-imidazol-4yl)ethyl]isothiourea) have been studied to explore the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist, N,N'-Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having Ki=1.5nM.

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