Antipsychotic agents differ in how fast they come off the dopamine D-2 receptors. Implications for atypical antipsychotic action

Rationale and objective: While the blockade of dopamine D-2 receptors are n ecessary for antipsychotic action, antipsychotic agents differ nearly a tho usand-fold in their affinity for the D-2 receptor. This affinity is determi ned by the rate at which the antipsychotic agent binds to (k(on)) and the r ate 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 t he affinity (K-1) of antipsychotic agents for the D-2 receptors, with parti cular reference to typical and atypical antipsychotic agents. Design: The k (off) of several typical as well as atypical antipsychotic agents (nemonapr ide, spiperone, haloperidol, chlorpromazine, raclopride, olanzapine, settin dole, clozapine and quetiapine) was measured in vitro using the H-3-radiola belled analogues of these drugs. The affinity of these drugs for the D-2 re ceptor 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 affin ity 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 rela tively little variation in k(on). The rate at which antipsychotic agents co me off the receptor (k(off)) accounted for 99% of the variation in their af finity for the D-2 receptor; differences in k(on) did not account for diffe rences in affinity. Conclusions: The differences in the affinity of antipsy chotic agents are entirely determined by how fast they come off the D-2 rec eptor. These differences in k(off) may lead to functionally different kinds of dopamine blockade. Drugs with a higher k(off) will be faster in blockin g receptors, and once blocked, will provide more access to surges in dopami ne transmission. Since atypical drugs show a lower affinity and a faster di ssociation, a higher k(off) for the D-2 receptor is proposed as a mechanism for "atypical" antipsychotic effect.