Alpha-[4-(1,1-Dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) inhibition of the in vitro binding of [3H]mepyramine to histamine H1-receptors prepared from guinea pig brain and ileum was characterized under several experimental conditions. After an intraperitoneal injection of 5 mg/kg of either terfenadine or chlorpheniramine, brain and ileum were obtained to determine in vitro the binding of [3H]mepyramine to histamine H1-receptors. While the binding of ligand to receptors from the ileum of both terfenadine and chlorpheniramine treated animals was almost completely inhibited, the ligand binding to receptors from brains of chlorpheniramine treated but not terfenadine treated animals was affected. When terfenadine was added to receptor homogenates from guinea pig brain and ileum, it antagonized the binding of [3H]mepyramine to receptors from both tissues. The potency of terfenadine antagonism of ligand binding was similar to both ileal (IC50, 200 nmol/l) and brain (IC50, 300 nmol/l) receptors. The kinetics of in vitro antagonism by terfenadine of [3H]mepyramine binding to receptors is unique in that antagonism of ligand binding by terfenadine was enhanced by a longer incubation of the receptors with this drug and H1-receptor blockade by terfenadine could not be reversed by extensive washing of these receptors at 25 degrees C. These results show that terfenadine treatment does not result in sufficient levels in the brain to inhibit central histamine receptors at a dose which overwhelmingly inhibits histamine receptors in peripheral tissue. It is proposed that terfenadine slowly associates with the H1-receptor and forms a stable complex from which it dissociates quite slowly.