PHARMACOLOGICAL ACTIVITY OF VUF 9153, AN ISOTHIOUREA HISTAMINE H-3 RECEPTOR ANTAGONIST

The pharmacological activity of the histamine H-3 receptor antagonist VUF 9153 (S-[3-(4(5)-imidazolyl)]propyl-N-(4-chlorobenzyl)isothiourea) has been investigated in vitro and in vivo. VUF 9153 displaced [H-3]N(alpha)-methylhistamine binding to rat cortex/ hippocampal membranes (pK(i) = 9.77 +/- 0.03) and antagonised the inhibitory responses to (R)-alpha-methylhistamine against electrical field stimulation in the isolated longitudinal smooth muscle preparation of guinea-pig ileum (pK(B) = 9.95 +/- 0.07). In these assays, VUF 9153 was 10-50-fold more potent than the prototype H-3 receptor antagonist thioperamide. VUF 9153 showed no or very weak activity in in vitro functional assays for histamine H-1 or H-2 receptors. Systemic administration of VUF 9153 (s.c. or p.o.) dose-dependently inhibited the ex vivo binding of [H-3]N(alpha)-methylhistamine to rat cortex/hippocampal membranes and dipsogenic responses induced by (R)-alpha-methylhistamine. Calculation of ED50 values, at the 1 h pretreatment time used, revealed that VUF 9153 administered s.c. or p.o., was approximately 2-fold weaker than thioperamide. These data indicate that, like thioperamide, VUF 9153 is a potent and selective antagonist for histamine H-3 receptors in vitro, possesses the ability to penetrate the blood-brain barrier to access central H-3 receptors and can inhibit H-3 receptor-mediated functional responses in vivo.