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In vivo receptor occupancy of N ‐desmethylclozapine (ACP‐104) and Clozapine
Author(s) -
Littler PeyLih H,
Schmelzer Kara R,
McFarland Krista,
Bonhaus Douglas W,
Lameh Jelveh
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1127.8
Subject(s) - clozapine , pharmacology , antipsychotic , agonist , in vivo , receptor , 5 ht receptor , atypical antipsychotic , schizophrenia (object oriented programming) , antipsychotic agent , typical antipsychotic , 5 ht2 receptor , serotonin , chemistry , medicine , biology , psychiatry , microbiology and biotechnology
Acadia is currently developing ACP‐104 ( N ‐desmethylclozapine, NDMC) as an antipsychotic with potential procognitive benefits. A number of clinical and preclinical lines of evidence suggest that NDMC, a predominant metabolite of clozapine, may contribute to clozapine's superior efficacy. Clozapine is an antagonist at serotonin 5‐HT 2A , muscarinic M 1, and dopamine D 2 receptors, while we have shown that ACP‐104 is an M 1 agonist and D 2 partial agonist. In vivo studies have shown that ACP‐104 has both antipsychotic and procognitive activity. We utilized ex vivo binding assays to study the in vivo receptor occupancy of clozapine and ACP‐104. In vivo binding to 5‐HT 2A and M 1 receptors was assessed in rat pre‐frontal cortex by [ 3 H] MDL100, 907 and [ 3 H] pirenzepine, respectively. Our data show that clozapine and ACP‐104 bind to cortical 5‐HT 2A receptors. Moreover, both ACP‐104 and clozapine bind to M 1 receptors in the prefrontal cortex. These data demonstrate that ACP‐104 interacts with 5‐HT 2A and M 1 receptors in vivo at doses that are effective in antipsychotic and procognitive animal models. Our findings support the potential utility of ACP‐104 as a procognitive antipsychotic agent in the treatment of schizophrenia.