The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine.
BACKGROUND
Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described.


OBJECTIVE
To comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay.


RESULTS
Profiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone.


CONCLUSIONS
The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.
Weiner
D M
DM
ACADIA Pharmaceuticals, Inc., 3911 Sorrento Valley Boulevard, San Diego, CA, USA. dweiner@acadia-pharm.com
Meltzer
H Y
HY
Veinbergs
I
I
Donohue
E M
EM
Spalding
T A
TA
Smith
T T
TT
Mohell
N
N
Harvey
S C
SC
Lameh
J
J
Nash
N
N
Vanover
K E
KE
Olsson
R
R
Jayathilake
K
K
Lee
M
M
Levey
A I
AI
Hacksell
U
U
Burstein
E S
ES
Davis
R E
RE
Brann
M R
MR
D000818:Animals; D016466:CHO Cells; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000494:pharmacology*; D041681:NIH 3T3 Cells; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000502:physiology
D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; C058272:norclozapine; D003024:Clozapine