Elucidating the role of muscarinic receptors in psychosis

In schizophrenia patients clozapine is metabolized in the liver to yield two major metabolites, desmethylclozapine's overall pharmacology remains largely unknown, although its structure suggests a promiscuous pharmacology like clozapine.

This may have functional consequences because a C417S point mutation in rat M1 was previously shown to affect receptor binding and coupling.

Fifteen single nucleotide polymorphisms (SNPs) were discovered, 9 of which are located in the coding region of the receptor.

Of these, 8 represent synonymous SNPs, indicating that CHRM1 is highly conserved in humans.

The unique profile of clozapine cannot be fully explained either by its 5HT receptors (7) as these characteristics are shared by other drugs (8).

Clozapine has a promiscuous pharmacology, interacts with many G protein-coupled receptors, and has nanomolar affinity for all five cloned muscarinic receptors (M1-M5) (8, 9).

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