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Analysis of molecular determinants of affinity and relative efficacy of a series of R ‐ and S ‐2‐(dipropylamino)tetralins at the 5‐HT 1A serotonin receptor
Ist Teil von
British journal of pharmacology, 2009-01, Vol.138 (6), p.1129-1139
Erscheinungsjahr
2009
Link zum Volltext
Quelle
Wiley Online Library
Beschreibungen/Notizen
Factors influencing agonist affinity and relative efficacy have been studied for the 5‐HT
1A
serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of
R
‐and
S
‐2‐(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5‐OH, 6‐OH, 7‐OH, 8‐OH) species).
Ligand binding studies were used to determine dissociation constants for agonist binding to the 5‐HT
1A
receptor:
K
i
values for agonists were determined in competition
versus
the binding of the agonist [
3
H]‐8‐OH DPAT. Competition data were all fitted best by a one‐binding site model.
K
i
values for agonists were also determined in competition
versus
the binding of the antagonist [
3
H]‐NAD‐199. Competition data were all fitted best by a two‐binding site model, and agonist affinities for the higher (
K
h
) and lower affinity (
K
l
) sites were determined.
The ability of the agonists to activate the 5‐HT
1A
receptor was determined using stimulation of [
35
S]‐GTP
γ
S binding. Maximal effects of agonists (
E
max
) and their potencies (EC
50
) were determined from concentration/response curves for stimulation of [
35
S]‐GTP
γ
S binding.
K
l
/K
h
determined from ligand binding assays correlated with the relative efficacy (relative
E
max
) of agonists determined in [
35
S]‐GTP
γ
S binding assays. There was also a correlation between
K
l
/K
h
and
K
l
/EC
50
for agonists determined from ligand binding and [
35
S]‐GTP
γ
S binding assays.
Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of
K
l
/
K
h
for predicting the relative efficacy of agonists.
British Journal of Pharmacology
(2003)
138
, 1129–1139. doi:
10.1038/sj.bjp.0705085