Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : ACADIA Pharmaceuticals Inc (ACAD) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (140)	6/14/2005 2:58:56 AM
From: tuck	Read Replies (1) \| Respond to of 588

[N-desmethylclozapine, an allosteric agonist at M1 receptor, potentiates NMDA receptor activity] Published online before print October 31, 2003, 10.1073/pnas.1835612100 PNAS \| November 11, 2003 \| vol. 100 \| no. 23 \| 13674-13679 N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity The molecular and neuronal substrates conferring on clozapine its unique and superior efficacy in the treatment of schizophrenia remain elusive. The interaction of clozapine with many G protein-coupled receptors is well documented but less is known about its biologically active metabolite, N-desmethylclozapine. Recent clinical and preclinical evidences of the antipsychotic activity of the muscarinic agonist xanomeline prompted us to investigate the effects of N-desmethylclozapine on cloned human M1-M5 muscarinic receptors. N-desmethylclozapine preferentially bound to M1 muscarinic receptors with an IC50 of 55 nM and was a more potent partial agonist (EC50, 115 nM and 50% of acetylcholine response) at this receptor than clozapine. Furthermore, pharmacological and site-directed mutagenesis studies suggested that N-desmethylclozapine preferentially activated M1 receptors by interacting with a site that does not fully overlap with the acetylcholine orthosteric site. As hypofunction of N-methyl-D-aspartate (NMDA) receptor-driven neuronal ensembles has been implicated in psychotic disorders, the neuronal activity of N-desmethylclozapine was electrophysiologically investigated in hippocampal rat brain slices. N-desmethylclozapine was shown to dose-dependently potentiate NMDA receptor currents in CA1 pyramidal cells by 53% at 100 nM, an effect largely mediated by activation of muscarinic receptors. Altogether, our observations provide direct evidence that the brain penetrant metabolite N-desmethylclozapine is a potent, allosteric agonist at human M1 receptors and is able to potentiate hippocampal NMDA receptor currents through M1 receptor activation. These observations raise the possibility that N-desmethylclozapine contributes to clozapine's clinical activity in schizophrenics through modulation of both muscarinic and glutamatergic neurotransmission.<< Full text freebie: pnas.org Interestingly, Merck apparently chose not to pursue this. I see no IP for them. Rick has already pointed to one application for Acadia, here's the latest: appft1.uspto.gov Cheers, Tuck PS Nice dig, Rick, on the FPRL1 patent application. Thanks. PPS Has anyone noticed that "Acadia" and "ACP" produce an annoying number of false hits in searches regarding the subject of this thread? Even boolean searches, where available, don't entirely fix the problem. Sigh.