The discovery of potent non-imidazole H3-receptor histamine antagonists

Histamine has been converted into a non-imidazole H(3)-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N(alpha) - position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a K(i) = 1.3 muM as an H(3) antagonist. Using this as a lead compound, a novel series of homologous 0 and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (K(i) = 0.18 +/- 0.10 muM, for [(3)H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of CN into the para position of the phenoxy group gave N-(5-p-cyanophenoxypropyl)piperidine. UCL 1980 (K(i) = 19 +/- 7 nM), ED(50) = 1.9 +/- 1.2 mg/kg per os in mice on brain tele-methylhistamine levels. Further optimisation of this structure gave UCL 2138, N-(3-p-cyanophenoxypropyl)piperidine. K(i)= 11 +/- 1.5 nM, ED(50) = 0.20 +/- 0.07 mg/kg.