The binding of conformationally restricted antihistamines to histamine receptors

Abstract

Abstract Some 1,1-diary 1–3-aminoprop-1-enes and 1,2-diaryl-4-amino-but-1-and −2-enes, including isomers of triprolidine and pyrrobutamine, have been prepared, their geometrical configurations established by pmr spectroscopy, and their affinities for histamine receptors measured on the guinea-pig ileum. These isomers differed considerably in their affinities and a particularly large difference was observed with the isomers of triprolidine (1170:1). This is because the binding of 3-aminoprop-1-enes is enhanced when α-pyridyl and aminomethyl groups are trans to one another or when p-tolyl and aminomethyl groups are cis, whereas activity is reduced when these groups are in opposite configurations. There is also a considerable difference between the geometrical isomers of pyrrobutamine (ca 200:1) but the most active compounds all have the same configuration whether 3-aminoprop-1-enes or 4-aminobut-2-enes. For high activity it appears necessary to have a trans Ar.C: CH.CH2.NC4H8 arrangement with the aromatic nucleus (α-pyridyl or phenyl) coplanar with the double bond, together with an aromatic function such as p-tolyl, benzyl or p-chlorobenzyl in a position cis to the aminomethyl group. All these compounds have restricted conformations so that the series serves as a useful model for the stereochemical requirements of the antihistamine receptor.