Rationale and objective: While the blockade of dopamine D2 receptors are necessary for antipsychotic action, antipsychotic agents differ nearly a thousand-fold in their affinity for the D2 receptor. This affinity is determined by the rate at which the antipsychotic agent binds to (kon) and the rate at which it dissociates from (koff) the D2 receptors. The objective of this study was to determine the relationship between kon, koff and the affinity (Ki) of antipsychotic agents for the D2 receptors, with particular reference to typical and atypical antipsychotic agents.
Design: The koff of several typical as well as atypical antipsychotic agents (nemonapride, spiperone, haloperidol, chlorpromazine, raclopride, olanzapine, sertindole, clozapine and quetiapine) was measured in vitro using the 3H-radiolabelled analogues of these drugs. The affinity of these drugs for the D2 receptor was determined by competition with 3H-raclopride in vitro. The kon was derived from values of affinity and ++koff.
Main outcome measures: kon, koff, and the Ki of antipsychotic drugs.
Results: The range of affinity values was similar to that conventionally accepted (0.025-155 nmol/L). The koff values varied a thousand-fold from 0.002 to 3.013 min-1, with relatively little variation in kon. The rate at which antipsychotic agents come off the receptor (koff) accounted for 99% of the variation in their affinity for the D2 receptor; differences in kon 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 D2 receptor. These differences in koff may lead to functionally different kinds of dopamine blockade. Drugs with a higher koff 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 koff for the D2 receptor is proposed as a mechanism for "atypical" antipsychotic effect.