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

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Abstract
A series of derivatives of 4‐methyldiphenhydramine have been examined as potential quaternary radioligands for the histamine H1‐receptor. [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. [3H]‐QMDP bound to H1‐receptors in a washed homogenate from guinea‐pig cerebellum with an affinity constant, Ka, of 1.14 ± 0.03 × 109 M−1. The proportion of non‐specific binding of 0.3–0.6 nM [3H]‐QMDP, defined by 0.4 μm 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 × 108 M−1, in rat cerebral cortex. Evidence was obtained for the presence of a secondary, non‐muscarinic, binding site for [3H]‐QMDP in guinea‐pig cerebellum, approximate Ka 1.5 × 107M−1, accounting for circa 4% of the total binding of 1 nM [3H]‐QMDP. 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. The potential utility of [3H]‐QMDP for studies of H1‐receptors in the plasma membrane of cells in culture is discussed.