S33084, a novel, potent, selective, and competitive antagonist at dopamine D(3)-receptors: I. Receptorial, electrophysiological and neurochemical profile compared with GR218,231 and L741,626.
The benzopyranopyrrole S33084 displayed pronounced affinity (pK(i) = 9.6) for cloned human hD(3)-receptors, and >100-fold lower affinity for hD(2) and all other receptors (>30) examined. S33084 concentration dependently, potently, and competitively (pA(2) = 9.7) antagonized dopamine (DA)-induced [(35)S]guanosine-5'- O-(3-thio)triphosphate (GTPgammaS) binding at hD(3)-receptors. It also concentration dependently abolished stimulation by DA of hD(3)-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 D(3)-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 hD(3)- versus hD(2)-receptor antagonist and its neurochemical and electrophysiological profiles were similar. In contrast, L741,626 was a preferential antagonist at hD(2) versus hD(3) 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 hD(3)-receptors. Although GR218,231 behaves similarly, L741,626 is a preferential D(2)-receptor antagonist. DA D(2)- but not D(3)-(auto) receptors tonically inhibit ascending dopaminergic pathways, although the latter may contribute to phasic suppression of DA release in frontal cortex.
Millan
M J
MJ
Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France.
Gobert
A
A
Newman-Tancredi
A
A
Lejeune
F
F
Cussac
D
D
Rivet
J M
JM
Audinot
V
V
Dubuffet
T
T
Lavielle
G
G
D000818:Animals; D001578:Benzopyrans / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004789:Enzyme Activation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000502:physiology; D050637:Receptors, Dopamine D3; D012701:Serotonin / Q000378:metabolism; D013450:Sulfones / Q000378:metabolism / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*
D001578:Benzopyrans; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; C408390:GR 218231; D007211:Indoles; D010078:Oxazines; D010880:Piperidines; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C408389:S 33084; D013450:Sulfones; D013764:Tetrahydronaphthalenes; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D020928:Mitogen-Activated Protein Kinases; D004298:Dopamine; D009638:Norepinephrine