(-)S amisulpride binds with high affinity to cloned dopamine D3 and D2 receptors

Amisulpride is a substituted benzamide antipsychotic with nanomolar affinity and high selectivity for dopamine D2 and dopamine D3 receptors. The interaction of racemic (+/-)RS amisulpride and its two enantiomers (+)R and (-)S with dopamine D2 and dopamine D3 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 D2long (hD2L) or the rat dopamine recombinant D3 (rD3) receptors. Ki values at dopamine rD3 receptors were similar regardless of the radioligand used, whereas at hD2L 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 hD2L and at dopamine rD3 receptors was similar. (-)S amisulpride displaced [3H]spiperone or [3H]nemonapride binding from both dopamine hD2L or dopamine rD3 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 rD3 receptor, respectively. The (+)R enantiomer has weaker affinity with respect to haloperidol for both dopamine hD2L and dopamine rD3 receptors. Our results show that (-)S amisulpride is the active enantiomer of amisulpride, showing high affinity for dopamine D3 and dopamine D2 receptors. © 2001 Elsevier Science B.V. All rights reserved.