Increasing D2 affinity results in the loss of clozapine's atypical antipsychotic action

Typical antipsychotics (haloperidol) give rise to severe motor side-effects while atypical antipsychotics like clozapine do not. Action at several neurotransmitter receptors have been implicated. To identify the critical mechanisms involved we synthesized an 8-Cl isomer of clozapine which showed an equivalent affinity to clozapine on multiple receptors (5-HT1A, 5-HT2, D-1, D-4, M-I) but differed in having a 10-fold higher affinity at the dopamine D-2/3 receptor. When tested in a series of animal models indicative of the typical/atypical distinction (catalepsy, striatal gene-induction, prolactin elevation) isoclozapine lost atypical properties and behaved like a typical antipsychotic. Simultaneous in vivo receptor occupancy studies confirmed that alterations in D-2 receptor occupancy were most closely related to loss of atypicality by clozapine's isomer isoclozapine. The implications for the design of future antipsychotics is discussed. NeuroReport 13:831-835 (C) 2002 Lippincott Williams Wilkins.