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Vol. 282, Issue 1, 181-191, 1997
-O-(3-thio)triphosphate Binding as
a Measure of Efficacy at Human Recombinant Dopamine D4.4
Receptors: Actions of Antiparkinsonian and Antipsychotic Agents
Department of Psychopharmacology, Institut de Recherches Servier,
78290 Croissy-sur-Seine, France
Recombinant human dopamine D4.4 receptor-mediated G protein
activation was characterized in membranes of transfected mammalian (Chinese hamster ovary) cells by the use of
[35S]guanosine-5
-O-(3-thio)triphosphate
([35S]GTP
S) binding. An initial series of experiments
defined the conditions (3 µM GDP, 100 mM NaCl, 3 mM
MgCl2) under which optimal stimulation (2.2-fold increase
in specific [35S]GTPS binding) was achieved with the
endogenous agonist dopamine. The number of dopamine-activated G
proteins in Chinese hamster ovary-D4.4 membranes was
determined through [35S]GTPS isotopic dilution
saturation binding, yielding a Bmax value of
2.29 pmol/mg. This compared with a D4.4 receptor
Bmax value of 1.40 pmol/mg determined by
[3H]spiperone saturation binding, indicating that 1 or 2 G proteins were activated per D4.4 receptor and that there
were few or no "spare receptors" in this cell line. Under these
conditions, the efficacy for stimulation of [35S]GTPS
binding at D4.4 receptors of 12 dopaminergic agonists was
determined. Several antiparkinsonian drugs, including ropinirole, quinerolane and lisuride, exhibited agonist activity at
D4.4 receptors (Emax = 74.3%,
72.4% and 32.2%, respectively, compared with dopamine = 100%).
The EC50 values for agonist stimulation of
[35S]GTPS binding correlated well with the inhibition
constants derived from competition binding with
[3H]spiperone (r = +.99). However, other
antiparkinsonian drugs (bromocriptine, L-DOPA and terguride) showed low
affinity and/or were devoid of agonist activity at D4.4
receptors. The potency at D4.4 receptors of the novel,
selective D4.4 receptor antagonist L 745,870 was
determined, indicating that it has high affinity (Ki = 1.99 nM) without detectable
agonist activity. Furthermore, L 745,870 completely inhibited
dopamine-stimulated [35S]GTPS binding with a
Kb value of 1.07 nM. The action of an additional 20 chemically diverse dopaminergic ligands, including clozapine, ziprasidone, sertindole, olanzapine and several other "atypical" antipsychotics, in advanced development was
investigated. Each of these ligands shifted the dopamine stimulation
curve to the right in a parallel manner consistent with competitive
antagonism at this site and yielding
Kb values (32.6, 22.4, 17.2 and
26.5 nM, respectively) that agreed closely with their
Ki values (38.0, 14.9, 18.5 and
26.1 nM). In contrast, raclopride and seroquel exhibited low affinity
at D4.4 receptors (Ki > 1000 nM). Other compounds that showed antagonist activity at D4.4 receptors included the
5-hydroxytryptamine2A receptor antagonist fananserin (RP
62203), the sigma ligand BMY 14,802 and the
D3 receptor antagonist GR 103,691. In conclusion, dopamine
D4.4 receptor activity is unlikely to be an important
factor in the clinical effectiveness of antiparkinsonian drugs,
although low agonist efficacy at D4.4 receptors might be
associated with a lesser incidence of side effects. Furthermore,
antagonist activity at D4.4 receptors is a common property
of many typical and atypical antipsychotic agents.
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