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Temperature‐dependence of the kinetics of the binding of [ 3 H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine to the histamine H 1 ‐receptor: comparison with the kinetics of [ 3 H]‐mepyramine
Author(s) -
Treherne J.M.,
Young J.M.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11592.x
Subject(s) - chemistry , kinetics , reaction rate constant , arrhenius equation , dissociation constant , histamine , dissociation (chemistry) , stereochemistry , receptor , histamine receptor , agonist , activation energy , biochemistry , endocrinology , biology , antagonist , physics , quantum mechanics
1 The dissociation of [ 3 H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine ([ 3 H]‐QMDP) from the histamine H 1 ‐receptor was markedly temperature‐dependent. The t 1/2 was 4 min at 37°C and 16 h at 6°C. The association rate constant, k 1 , was also temperature‐dependent, but not to the same extent as k ‐1 . 2 Plots of the observed rate constant for [ 3 H]‐QMDP‐receptor complex formation, k on , versus [ 3 H‐QMDP] were linear at both 30°C and 10°C, consistent with the interaction of [ 3 H]‐QMDP with the H 1 ‐receptor being a simple, one‐step equilibrium. 3 The ratio of the kinetic constants, k 1 / k ‐1 , indicated that the affinity constant of [ 3 H]‐QMDP for the H 1 ‐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°C, 30°C and 25°C provided some evidence that the affinity of (+)‐QMDP is greater at 25°C than 37°C. However, the flattening of the concentration‐response curves for histamine at low concentrations of (+)‐QMDP at 30°C and 25°C is consistent with a slow dissociation of the (+)‐QMDP‐receptor complex and hence an incomplete equilibration with the agonist. 4 Arrhenius plots for k 1 and k ‐1 for [ 3 H]‐QMDP were linear between 37°C and 6°C. The activation energies, E a , 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 [ 3 H]‐mepyramine from the H 1 ‐receptor was also linear between 37°C and 6°C. The activation energy was 140 ± 2 kJ mol −1 . 6 Activation energies for complex formation with the H 1 ‐receptor, E af , and complex dissociation, E ad , were similar for [ 3 H]‐QMDP and [ 3 H]‐mepyramine. The energy difference, E af — E ad , equivalent to the enthalpy change, did not differ significantly for the two ligands (‐52 and −48 kJ mol −1 , respectively). The larger values of k 1 and k ‐1 for [ 3 H]‐mepyramine compared to [ 3 H]‐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‐H 1 ‐receptor interaction. This would be entropically more favourable for [ 3 H]‐mepyramine, a tertiary amine, than for [ 3 H]‐QMDP, a quaternary amine.