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17 juillet 2005
J Pharmacol Exp Ther
2000; 239; 3; 1048-1062
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.
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J Pharmacol Exp Ther
2000; 293; 3; 1063-1073
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.
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