(Partial) agonist/antagonist properties of novel diarylalkyl carbamates on histamine H3 receptors.

In the search for new ligands of the histamine H-3 receptor, novel diarylalkyl carbamates (1-19) were synthesized as derivatives of 3-(1H-imidazol-4-yl)propanol and -ethanol. Carbamates were built up via isocyanates either from corresponding amines by reaction with diphosgene or from related carboxylic acid/diphenylphosphoryl azide and the alcoholic component. Sterically hindered amines were prepared in a two-step reaction sequence from corresponding ketones. Some of the title compounds showed (partial) agonist activity at the histamine H-3 receptor in vitro and in vivo. Diphenylmethyl carbamate 2 was identified as a new lead structure (ED50 = 5.3 +/- 2.6 mg/kg po, alpha = 1.0). Aromatic substitution in ortho- or para-positions of 2 led to a loss of agonist activity, meta-Substitution was tolerated to some extent. These effects seemed to be caused by steric rather than electronic proper ties of the substituents. An investigation of exchange of one or both phenyl rings of 2 by heterocyclic rings led to the highly active and selective thienyl derivative 18 (ED50 = 3.4 +/- 1.4 mg/kg po, alpha = 1.0). These new (partial) agonists of the histamine H-3 receptor might serve as pharmacological tools for investigating molecular aspects of the H-3 receptor or as possible centrally acting therapeutic agents with oral bioavailability. (C) 2000 Elsevier Science Ltd. All rights reserved.