UNIQUE BINDING CHARACTERISTICS OF ANTIPSYCHOTIC AGENTS INTERACTING WITH HUMAN DOPAMINE D(2A), D(2B), AND D(3) RECEPTORS

In the present study we have compared the pharmacological properties o f human dopamine (DA) D2A, D2B, and D3 receptors expressed in mammalia n cell lines, using [H-3]raclopride as a radioligand. Most of the comp ounds tested had about equal affinity for D2A and D3 receptors, with t he exception of remoxipride, which displayed a 10-fold D2 selectivity, and the aminotetralin (+)UH 232, which displayed a 5-fold D3 selectiv ity. Several antipsychotic agents, including clozapine and substituted benzamides, bound with 2-3-fold higher affinity to the D2B (short) th an to the D2A (long) isoform, whereas others failed to differentiate b etween the two isoforms. The atypical antipsychotic agent clozapine bo und in a biphasic manner and with unexpectedly high affinity (35 nm) t o the D2, receptor, suggesting that clozapine may not be as D4 selecti ve as reported previously. In addition, remoxipride, a new antipsychot ic agent with low potential to produce extrapyramidal side effects, di splayed 2-3-fold higher affinity for the D2B receptor than for the D2, receptor. Furthermore, sodium differently regulated clozapine and ben zamide binding to the various DA receptor subtypes. Thus, sodium decre ased 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 increas ed by sodium. Whether the unique characteristics of the binding of clo zapine and benzamides to cloned DA receptors demonstrated in the prese nt study are related to the favorable clinical properties of these com pounds remains to be elucidated.