[AC260584 -- Differential effects of M1 and 5-HT1A receptors on atypical antipsychotic drug-induced dopamine efflux in the medial prefrontal cortex.]
Considering that Acadia saw fit to mention this compound in a PR last year, and that they now have a pipeline page on their website (maybe they got tired of my grousing about that lack here), I find it odd that this compound is not mentioned on the latter . . .
acadia-pharm.com
>>J Pharmacol Exp Ther. 2009 Jun 2. [Epub ahead of print]
Differential effects of M1 and 5-HT1A receptors on atypical antipsychotic drug-induced dopamine efflux in the medial prefrontal cortex.
Li Z, Prus AJ, Dai J, Meltzer HY.
Vanderbilt University.
Systemic administration of the M1 receptor agonists N-desmethylclozapine (NDMC) and AC260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one) increase dopamine (DA) efflux in rat medial prefrontal cortex (mPFC). This increase is blocked by systemic administration of both telenzepine, a preferential M1 receptor antagonist, and WAY 100635, a 5-HT1A receptor antagonist. The present study sought to determine if DA efflux in the mPFC induced by the atypical antipsychotic drugs (APDs) clozapine, risperidone and olanzapine is also mediated by M1 receptor stimulation, and specifically, to determine if these effects are mediated M1 receptors in the mPFC, through using in vivo microdialysis in awake, freely-moving Sprague-Dawley rats. Telenzepine (3 mg/kg) significantly attenuated clozapine (20 mg/kg)-, olanzapine (10 mg/kg)- and risperidone (1.0 mg/kg)-induced increases in mPFC DA efflux. Local mPFC perfusion of NDMC, AC260584, clozapine, risperidone or olanzapine (10 - 500 microM), significantly increased DA efflux in the mPFC. Local mPFC perfusion of telenzepine (0.1 microM) prevented increases in mPFC DA efflux induced by systemic administration of AC260584 (10 mg/kg), NDMC (20 mg/kg) and clozapine (10 mg/kg), but not by risperidone (1.0 mg/kg) or olanzapine (10 mg/kg). However, local mPFC perfusion of WAY100635 (0.1 microM) prevented mPFC DA efflux induced by clozapine, risperidone and olanzapine, but not by AC260584 or NDMC. These results suggest that the AC260584-, NDMC - and clozapine-induced DA efflux in the mPFC is directly mediated by mPFC M1 receptors.<<
This is a full text freebie:
jpet.aspetjournals.org
Use of various receptor agonists and antagonists in this study seem to suggest that stimulation of the muscarinic M1 receptor might be a good idea, contributing more to cognitive improvement (as opposed to anti-psychotic properties) in treatment of such neurological diseases as schizophrenia and AD than was previously thought. Or so I gather; I don't think the idea is new, but the authors call it a promising new target and immediately cite research spanning a decade to support that idea. Guess it depends on your definition of "new" in this context.
Anyhow, the pipeline compound that does this is AM-831, being developed in Japan and Asia by Meiji Seika Kaisha pursuant to a licensing agreement of a few months ago. Still preclinical, though. In addition to M1 agonism, it also antagonizes dopamine and serotonin receptors, to address the psychotic side of the above mentioned diseases, & sings "Happy Birthday." Kind of reminds me of Gilead's three in one antivirals . . .
The multiple target approach of AM-831 might explain why AC260584 is apparently not being developed, as it only hits one measly target that other drugs already hit, and apparently wasn't much more advanced in development. So why not not offload your inventory of the useless thing on your collaborator for research purposes? Might even be able to write it off . . .
Actually, the summary is worth a look for hints as to why NDMC did not work. Apparently its effects in the prefrontal cortex require clozapine!
Cheers, Tuck |
