Temperature-dependence of the kinetics of the binding of [3H]-(+)-N-methyl-4-methyldiphenhydramine to the histamine H1-receptor: comparison with the kinetics of [3H]-mepyramine.

1. The dissociation of [3H]-(+)-N-methyl-4-methyldiphenhydramine ([3H]-QMDP) from the histamine H1-receptor was markedly temperature-dependent. The t1/2 was 4 min at 37 degrees C and 16 h at 6 degrees C. The association rate constant, k1, was also temperature-dependent, but not to the same extent as k-1. 2. Plots of the observed rate constant for [3H]-QMDP-receptor complex formation, kon, versus [3H-QMDP] were linear at both 30 degrees C and 10 degrees C, consistent with the interaction of [3H]-QMDP with the H1-receptor being a simple, one-step equilibrium. 3. The ratio of the kinetic constants, k1/k-1, indicated that the affinity constant of [3H]-QMDP for the H1-receptor should increase with decreasing temperature. Measurement of (+)-QMDP antagonism of the contraction of longitudinal muscle strips from guinea-pig small intestine induced by histamine at 37 degrees C, 30 degrees C and 25 degrees C provided some evidence that the affinity of (+)-QMDP is greater at 25 degrees C than 37 degrees C. However, the flattening of the concentration-response curves for histamine at low concentrations of (+)-QMDP at 30 degrees C and 25 degrees C is consistent with a slow dissociation of the (+)-QMDP-receptor complex and hence an incomplete equilibration with the agonist. 4. Arrhenius plots for k1 and k-1 for [3H]-QMDP were linear between 37 degrees C and 6 degrees C. The activation energies, Ea, for complex formation and dissociation were 77 +/- 4 and 129 +/- 3 kJ mol-1, respectively. 5. An Arrhenius plot for k-1 for the dissociation of [3H]-mepyramine from the H1-receptor was also linear between 37 degrees C and 6 degrees C. The activation energy was 140 +/- 2 kJ mol-1. 6. Activation energies for complex formation with the H1-receptor, Eaf, and complex dissociation, Ead, were similar for [3H]-QMDP and [3H]-mepyramine. The energy difference, Eaf--Ead, equivalent to the enthalpy change, did not differ significantly for the two ligands (-52 and -48 kJ mol-1, respectively). The larger values of k1 and k-1 for [3H]-mepyramine compared to [3H]-QMDP imply the presence of an entropic component in the interaction. 7. The simplest explanation for these observations is that transfer from the aqueous phase into a hydrophobic region is a significant factor in antagonist-H1-receptor interaction. This would be entropically more favourable for [3H]-mepyramine, a tertiary amine, than for [3H]-QMDP, a quaternary amine.