Synthesis of potent non-imidazole histamine H-3-receptor antagonists

Histamine has been converted into a non-imidazole H-receptor histamine anta gonist by addition of a 3-phenylbutyl group at the N-alpha-position followe d by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-ph enylbutyl)amine, remarkably has a K-i = 1.3 mu M as an H-3 antagonist. Usin g this as a lead compound, a novel series of homologous O and S isosteric t ertiary amines was synthesised and structure-activity studies furnished N-( 5-phenoxypentyl)pyrrolidine (K-i = 0.18 +/- 0.10 mu M, for [H-3]histamine r elease from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the pam position of the phenoxy gr oup gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (K-i = 39 +/- 11 n M), ED50 = 1.1 +/- 0.6 mg/kg per as in mice on brain tele-methylhistamine l evels.