Zolantidine (SK&F 95282) is a potent selective brain-penetrating histamine H2-receptor antagonist

1. The novel benzthiazole derivative zolantidine (SK&F 95282) is a potent antagonist of histamine at H2-receptors in guinea-pig atrium and rat uterus. Only apparent pA2 values of 7.46 and 7.26 respectively could be calculated since the slopes of the Schild plots were significantly less than unity. 2. Zolantidine is equally potent as an antagonist at histamine H2-receptors in guinea-pig brain. The compound inhibited histamine stimulated Adenylate Cyclase (pKi 7.3) and dimaprit stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation (approx pA2 7.63), and competed with [3H]-tiotidine binding (pKi 7.17). 3. Zolantidine is at least 30 fold more potent at H2-receptors than at other peripheral and central receptors investigated. 4. Infusion of zolantidine into rats produces a brain concentration greater than the plateau blood concentration (brain/blood ratio 1.45). 5. Zolantidine is thus characterized as a potent selective brain-penetrating H2-receptor antagonist, and will be a valuable pharmacological tool for investigating possible physiological and pathological roles for histamine in the central nervous system.