S33084, a novel, potent, selective, and competitive antagonist at dopamineD-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) f or cloned human hD(3)-receptors, and >100-fold lower affinity for hD(2) and all other receptors (>30) examined. S33084 concentration dependently, pote ntly, and competitively (pA(2)= 9.7) antagonized dopamine (DA)-induced [S-3 5]guanosine-5'- O-(3-thio)triphosphate (GTP gamma S) binding at hD(3)-recep tors. It also concentration dependently abolished stimulation by DA of hD(3 )-receptor-coupled mitogen-activated protein kinase. Administered alone, S3 3084 did not modify dialysate levels of DA in the frontal cortex, nucleus a ccumbens, or striatum of freely moving rats, nor the firing rate of ventrot egmental dopaminergic cell bodies. Furthermore, it had minimal effect on DA turn-over in mesocortical, mesolimbic, and nigrostriatal projection region s. However, S33084 dose dependently blocked the suppressive influence of th e preferential D-3-agonist PD128,907 on frontocortical release of DA. Furth ermore, it likewise antagonized the inhibitory influence of PD128,907 on th e electrical activity of ventrotegmental dopaminergic neurons. Although les s potent than S33084, GR218,231 likewise behaved as a selective hD(3)- vers us 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 in creased frontocortical, mesolimbic, and (more potently) striatal DA release , enhanced the firing rate of dopaminergic perikarya, and accelerated cereb ral DA synthesis. It also blocked the actions of PD128,907. In conclusion, S33084 is a novel, potent, selective, and competitive antagonist at hD(3)-r eceptors. Although GR218,231 behaves similarly, L741,626 is a preferential D-2-receptor antagonist. DA D-2- but not D-3-(auto) receptors tonically inh ibit ascending dopaminergic pathways, although the latter may contribute to phasic suppression of DA release in frontal cortex.