Antipsychotic agents differ in how fast they come off the dopamine D2 receptors.: Implications for atypical antipsychotic action

Rationale and objective: While the blockade of dopamine D-2 receptors are necessary for antipsychotic action, antipsychotic agents differ nearly a thousand-fold in their affinity for the D-2 receptor. This affinity is determined by the rate at which the antipsychotic agent binds to (k(on)) and the rate at which it dissociates from (k(off)) the D-2 receptors. The objective of this study was to determine the relationship between k(on), k(off) and the affinity (K-1) of antipsychotic agents for the D-2 receptors, with particular reference to typical and atypical antipsychotic agents. Design: The k(off) of several typical as well as atypical antipsychotic agents (nemonapride, spiperone, haloperidol, chlorpromazine, raclopride, olanzapine, settindole, clozapine and quetiapine) was measured in vitro using the H-3-radiolabelled analogues of these drugs. The affinity of these drugs for the D-2 receptor was determined by competition with H-3-raclopride in vitro. The k(on) was derived from values of affinity and k(off). Main outcome measures: k(on), k(off) and the K-1 of antipsychotic drugs. Results: The range of affinity values was similar to that conventionally accepted (0.025-155 nmol/L). The Ig,values varied a thousand-fold from 0.002 to 3.013 min(-1), with relatively little variation in k(on). The rate at which antipsychotic agents come off the receptor (k(off)) accounted for 99% of the variation in their affinity for the D-2 receptor; differences in k(on) did not account for differences in affinity. Conclusions: The differences in the affinity of antipsychotic agents are entirely determined by how fast they come off the D-2 receptor. These differences in k(off) may lead to functionally different kinds of dopamine blockade. Drugs with a higher k(off) will be faster in blocking receptors, and once blocked, will provide more access to surges in dopamine transmission. Since atypical drugs show a lower affinity and a faster dissociation, a higher k(off) for the D-2 receptor is proposed as a mechanism for "atypical" antipsychotic effect.