[3H]-(+)-N-methyl-4-methyldiphenhydramine, a quaternary radioligand for the histamine H1-receptor.

1. A series of derivatives of 4-methyldiphenhydramine have been examined as potential quaternary radioligands for the histamine H1-receptor. 2. [3H]-(+)-N-methyl-4-methyldiphenhydramine ([3H]-QMDP), 83 Ci mmol-1, was synthesized by methylation of the tertiary analogue and purified by high-voltage electrophoresis. 3. [3H]-QMDP bound to H1-receptors in a washed homogenate from guinea-pig cerebellum with an affinity constant, Ka, of 1.14 +/- 0.03 x 10(9) M-1. The proportion of non-specific binding of 0.3-0.6 nM [3H]-QMDP, defined by 0.4 microM mepyramine, was usually in the range 15-45%, depending on the method of measurement of binding. The affinity of [3H]-QMDP was similar in guinea-pig cerebellum, cerebral cortex and hippocampus, but was lower, 1.4 x 10(8) M-1, in rat cerebral cortex. 4. Evidence was obtained for the presence of a secondary, non-muscarinic, binding site for [3H]-QMDP in guinea-pig cerebellum, approximate Ka 1.5 x 10(7) M-1, accounting for circa 4% of the total binding of 1 nM [3H]-QMDP. 5. There was a very good correlation between the affinities of 15 compounds for the H1-receptor determined from inhibition of [3H]-QMDP binding and from inhibition of [3H]-mepyramine binding. 6. The potential utility of [3H]-QMDP for studies of H1-receptors in the plasma membrane of cells in culture is discussed.