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-C1 isomer of clozapine which showed an equivalent affinity to clozapine on multiple receptors (5-HT1A, 5-HT2, D1, D4, M1) but differed in having a 10-fold higher affinity at the dopamine D2/3 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 D2 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.
Kapur
Shitij
S
Department of Psychiatry, University of Toronto, Toronto M5S 3H6, Canada.
McClelland
Robert A
RA
VanderSpek
Susan C
SC
Wadenberg
Marie-Louise G
ML
Baker
Glen
G
Nobrega
Jose
J
Zipursky
Robert B
RB
Seeman
Philip
P
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D007536:Isomerism; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; D011388:Prolactin; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine