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Thermodynamic analysis of agonist and antagonist binding to the chicken brain melatonin receptor
Author(s) -
Chong Nelson W.S.,
Sugden David
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.tb14059.x
Subject(s) - luzindole , melatonin receptor , chemistry , melatonin , gtp' , agonist , enthalpy , partial agonist , receptor , binding site , guanosine , stereochemistry , biophysics , endocrinology , biochemistry , thermodynamics , biology , physics , enzyme
1 The binding of 2‐[ 125 I]‐iodomelatonin to chicken brain membranes, and the inhibition of binding by melatonin, N‐acetyltryptamine and luzindole, were examined at temperatures between 4°C and 37°C. 2 At all temperatures studied, the binding affinity ( K d or K j ) for 2‐[ 125 I]‐iodomelatonin, melatonin (both agonists) and, to a lesser extent, N‐acetyltryptamine (a partial agonist) was reduced by inclusion of guanosine triphosphate (GTP, 1 mM) in the assay. GTP did not affect the K i for luzindole, a melatonin receptor antagonist. 3 The maximal density of binding sites ( B max ) was not affected by temperature but the K d showed a peak at 21°C with lower values at both higher and lower temperatures giving curvilinear van't Hoff plots (ln K A vs 1/temperature). 4 Derived changes in entropy (ΔS 0 ;) and enthalpy (ΔH 0 ;) of binding for all of the melatonin ligands decreased as temperature increased. 5 The affinity, and thus the free energy of binding, ΔG 0 ;, of these ligands at the melatonin receptor have identical values at several temperatures yet at these temperatures ΔS 0 ; and ΔH 0 ; were very different, implying that more than one intermolecular force must be involved in the binding of ligand and receptor. 6 Conceivably, the large positive ΔS 0 ; observed at low temperatures, perhaps as a result of hydrophobic interactions, is compensated by a corresponding, but opposite, change in enthalpy at higher temperatures. However, it is not clear what type of binding force(s) would show such a temperature‐dependence. 7 These studies suggest that caution must be exercised in the molecular interpretation of derived measures of ΔS 0 and ΔH 0 obtained from direct measurements of ΔG 0 .