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Modulation of antagonist binding to histamine H 1 ‐receptors by sodium ions and by 2‐amino‐2‐hydroxymethyl‐propan‐1,3‐diol HCl
Author(s) -
Gibson W.J.,
Roques T.W.,
Young J.M.
Publication year - 1994
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.1476-5381.1994.tb14882.x
Subject(s) - mepyramine , tris , chemistry , hydroxymethyl , histamine , binding site , stereochemistry , antagonist , receptor , biochemistry , biology , endocrinology
1 NaCl (100 m m ) reduced the potency of (+)‐N‐methyl‐4‐methyldiphenhydramine ((+)‐QMDP) as an inhibitor of the binding of [ 3 H]‐mepyramine to histamine H 1 ‐receptors on guinea‐pig cerebellar membranes to a greater extent than that of mepyramine, consistent with the greater inhibitory effect of Na + on the binding of [ 3 H]‐QMDP than on the binding of [ 3 H]‐mepyramine. 2 The concentration of 2‐amino‐2‐hydroxymethyl‐propan‐1,3‐diol HCl (Tris, HCl) buffer, pH 7.5, present had little effect on the temelastine‐insensitive binding of [ 3 H]‐mepyramine, but caused a concentration‐dependent inhibition of the binding of [ 3 H]‐mepyramine sensitive to 1 μ m temelastine (H 1 ‐receptor binding), with an approximate IC 50 of 75 m m , assuming that complete inhibition would have been achieved. 3 Inhibition of [ 3 H]‐mepyramine binding by Na + was more marked in 10 m m than in 50 m m Tris HCl and was not evident in 200 m m Tris HCl. 4 The K d for the temelastine‐sensitive binding of [ 3 H]‐mepyramine measured in 10 m m Tris HCl, 0.24 ± 0.01 n m , was increased by 2.2 ± 0.2 fold by 100 m m NaCl, without any significant change in the maximum binding ( B max ). The B max for [ 3 H]‐mepyramine was similarly unchanged in 50 m m Tris HCl, but the K d was increased 2.5 ± 0.2 fold. 5 The K d for the temelastine‐sensitive binding of [ 3 H]‐mepyramine was also increased in 50 m m , compared with 10 m m , N‐[2‐hydroxyethyl]piperazine‐N′‐[2‐ethanesulphonic acid] KOH (HEPES.KOH) buffer ( K d 0.25 ± 0.02 n m in 10 m m HEPES), but the evidence for an interaction between HEPES and Na + was less clear. 6 The effect of 100 m m NaCl on the inhibition of [ 3 H]‐mepyramine binding in 10 m m Tris HCl was examined for a range of antagonists. The decrease in potency caused by Na + was greatest for triprolidine, (+)‐chlorpheniramine and benzilylcholine (9.6–10.3 fold increase in K d values) but the binding of mepyramine and promethazine was much less affected (1.8 and 1.9 fold increase in K d respectively). The K d for temelastine was not significantly changed. In contrast to the general decrease in antagonist affinity in the presence of Na + , the K d for MDL 16,455A (4‐[1‐hydroxy‐4‐[4‐(hydroxydiphenylmethyl)‐1‐piperidinyl]butyl]‐α,α‐dimethylbenzene acetic acid) was increased, but only by 1.5 fold. 7 It is concluded that Na + can act as an allosteric effector of the binding of antagonists at the histamine H 1 ‐receptor. Tris HCl also appears to have an allosteric action at the H 1 ‐receptor.