(-)S amisulpride binds with high affinity to cloned dopamine D(3) and D(2) receptors.
Amisulpride is a substituted benzamide antipsychotic with nanomolar affinity and high selectivity for dopamine D(2) and dopamine D(3) receptors. The interaction of racemic (+/-)RS amisulpride and its two enantiomers (+)R and (-)S with dopamine D(2) and dopamine D(3) receptors subtypes were compared with that of haloperidol. Binding studies were performed using either [3H]spiperone or [3H]nemonapride in baculovirus/Spodoptera frugiperda insect (Sf-9) cell system expressing either the human dopamine recombinant D(2)long (hD(2L)) or the rat dopamine recombinant D(3) (rD(3)) receptors. K(i) values at dopamine rD(3) receptors were similar regardless of the radioligand used, whereas at hD(2L) receptors values were higher using [3H]spiperone than [3H]nemonapride. However, the rank order of compound potency against radiolabeled spiperone or nemonapride both at dopamine hD(2L) and at dopamine rD(3) receptors was similar. (-)S amisulpride displaced [3H]spiperone or [3H]nemonapride binding from both dopamine hD(2L) or dopamine rD(3) receptors, being twofold more potent than the racemic form and 38-19-fold more potent than (+)R enantiomer. Both racemic and the (-)S enantiomer exhibited 2-4 ([3H]spiperone)- and 3-4 ([3H]nemonapride)-fold higher affinity than haloperidol for dopamine rD(3) receptor, respectively. The (+)R enantiomer has weaker affinity with respect to haloperidol for both dopamine hD(2L) and dopamine rD(3) receptors. Our results show that (-)S amisulpride is the active enantiomer of amisulpride, showing high affinity for dopamine D(3) and dopamine D(2) receptors.
Castelli
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Neuroscienze S.c.a r.l., Via Palabanda 9, 09124-I, Cagliari, Italy. castelli@unica.it
Mocci
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Sanna
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Gessa
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Pani
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D000077582:Amisulpride; D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D004274:DNA, Recombinant / Q000235:genetics; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D013134:Spiperone / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D014316:Tritium
D001549:Benzamides; D004274:DNA, Recombinant; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D014316:Tritium; D013134:Spiperone; D013469:Sulpiride; D000077582:Amisulpride; C030265:nemonapride