Unique binding characteristics of antipsychotic agents interacting with human dopamine D2A, D2B, and D3 receptors.

In the present study we have compared the pharmacological properties of human dopamine (DA) D2A, D2B, and D3 receptors expressed in mammalian cell lines, using [3H]raclopride as a radioligand. Most of the compounds tested had about equal affinity for D2A and D3 receptors, with the exception of remoxipride, which displayed a 10-fold D2 selectivity, and the aminotetralin (+)-UH 232, which displayed a 5-fold D3 selectivity. Several antipsychotic agents, including clozapine and substituted benzamides, bound with 2-3-fold higher to the D2B (short) than to the D2A (long) isoform, whereas others failed to differentiate between the two isoforms. The atypical antipsychotic agent clozapine bound in a biphasic manner and with unexpectedly high affinity (35 nM) to the D2B receptor, suggesting that clozapine may not be as D4 selective as reported previously. In addition, remoxipride, a new antipsychotic agent with low potential to produce extrapyramidal side effects, displayed 2-3-fold higher affinity for the D2B receptor than for the D2A receptor. Furthermore, sodium differently regulated clozapine and benzamide binding to the various DA receptor subtypes. Thus, sodium decreased the affinity of clozapine for D2A and D2B receptors about 3-fold, whereas the affinity for D3 receptors was unaltered. In contrast, the affinity of raclopride for the three DA receptor subtypes was increased by sodium. Whether the unique characteristics of the binding of clozapine and benzamides to cloned DA receptors demonstrated in the present study are related to the favorable clinical properties of these compounds remains to be elucidated.