S33084, a
Novel, Potent, Selective, and Competitive
Antagonist at Dopamine D3-Receptors:
I. Receptorial, Electrophysiological and
Neurochemical Profile Compared with GR218,231
and L741,626
Mark J. Millan, Alain
Gobert, et
al.
Institut de Recherches
Servier, Centre de Recherches de Croissy, Paris,
France
The benzopyranopyrrole S33084 displayed
pronounced affinity (pKi = 9.6) for
cloned human hD3-receptors, and >100-fold
lower affinity for hD2 and all other receptors
(>30) examined. S33084 concentration
dependently, potently, and competitively
(pA2 = 9.7) antagonized dopamine
(DA)-induced [35S]guanosine-5'-
O-(3-thio)triphosphate (GTPS) binding at
hD3-receptors.
It also concentration dependently abolished
stimulation by DA of hD3-receptor-coupled
mitogen-activated protein kinase. Administered
alone, S33084 did not modify dialysate levels of
DA in the frontal cortex, nucleus accumbens, or
striatum of freely moving rats, nor the firing
rate of ventrotegmental dopaminergic cell
bodies. Furthermore, it had minimal effect on DA
turnover in mesocortical, mesolimbic, and
nigrostriatal projection regions. However,
S33084 dose dependently blocked the suppressive
influence of the preferential D3-agonist
PD128,907 on frontocortical release of DA.
Furthermore, it likewise antagonized the
inhibitory influence of PD128,907 on the
electrical activity of ventrotegmental
dopaminergic neurons. Although less potent than
S33084, GR218,231 likewise behaved as a
selective hD3- versus hD2-receptor antagonist
and its neurochemical and electrophysiological
profiles were similar. In contrast, L741,626 was
a preferential antagonist at hD2 versus hD3
sites.
In vivo, on administration alone, L741,626
increased frontocortical, mesolimbic, and (more
potently) striatal DA release, enhanced the
firing rate of dopaminergic perikarya, and
accelerated cerebral DA synthesis. It also
blocked the actions of PD128,907. In conclusion,
S33084 is a novel, potent, selective, and
competitive antagonist at hD3-receptors.
Although GR218,231 behaves similarly,
L741,626 is a preferential D2-receptor
antagonist. DA D2- but not D3-(auto) receptors
tonically inhibit ascending dopaminergic
pathways, although the latter may contribute to
phasic suppression of DA release in frontal
cortex.
S33084,
a novel, potent, selective, and competitive
antagonist at dopamine D(3)-receptors: II.
Functional and behavioral profile compared with
GR218,231 and L741,626
Millan MJ, Dekeyne A,
The selective dopamine D(3)-receptor
antagonist S33084 dose dependently attenuated
induction of hypothermia by
7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT)
and PD128,907. S33084 also dose dependently
reduced 7-OH-DPAT-induced penile erections (PEs)
but had little effect on 7-OH-DPAT-induced
yawning and hypophagia, and it did not block
contralateral rotation elicited by the
preferential D(3) agonist quinpirole in
unilateral substantia nigra-lesioned rats.
In models of potential antipsychotic
activity, S33084 had little effect on
conditioned avoidance behavior and the locomotor
response to amphetamine and cocaine in rats, and
weakly inhibited apomorphine-induced climbing in
mice. Moreover, S33084 was inactive in models of
potential extrapyramidal activity in rats:
induction of catalepsy and prolactin secretion
and inhibition of methylphenidate-induced
gnawing.
Another selective D(3) antagonist,
GR218,231, mimicked S33084 in inhibiting
7-OH-DPAT-induced PEs and hypothermia but
neither hypophagia nor yawning behavior.
Similarly, it was inactive in models of
potential antipsychotic and extrapyramidal
activity. In distinction to S33084 and
GR218,231, the preferential D(2) antagonist
L741,626 inhibited all responses elicited by
7-OH-DPAT.
Furthermore, it displayed robust activity in
models of antipsychotic and, at slightly higher
doses, extrapyramidal activity. In summary,
S33084 was inactive in models of potential
antipsychotic and extrapyramidal activity and
failed to modify spontaneous locomotor behavior.
Furthermore, it did not affect hypophagia or
yawns, but attenuated hypothermia and
PEs, elicited by 7-OH-DPAT.
This profile was shared by GR218,231,
whereas L741,626 was effective in all models.
Thus, D(2)-receptors are principally involved in
these paradigms, although D(3)-receptors may
contribute to induction of hypothermia and PEs.
S33084 should comprise a useful tool for further
exploration of the pathophysiological
significance of D(3)- versus
D(2)-receptors.
