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 (360)	11/18/2006 12:02:56 PM
From: dr.praveen	Read Replies (1) \| Respond to of 588

"Shopping for a four wheel drive Tacoma today. Somebody stop me." Have a test drive with Honda Ridgeline too. Looks cool and has very good reviews... Edit: It has got Motor trend Truck of the year award in 2006 if that tempts you:-)

To: scaram(o)uche who wrote (360)	11/18/2006 12:33:36 PM
From: tuck	Read Replies (1) \| Respond to of 588

>>Are you asking if 103 might also lock the receptor into its inactive form, and thus contribute to cardio side-effects? I believe that the answer is "yes", but we don't know anything more from this abstract than before?? I guess that I don't understand what you're asking.... we knew that 103 was an inverse agonist, and we knew that 2A is expressed on cv tissue.<< Yes, that's what I was asking. didn't realize the cv side effects were an issue with "highly selective" 5-HT2a inverse agonists, too. Common knowledge if you're paying attention? If so, sorry for wasting your time, but I appreciate the answer. >> aren't we baseline concerned about cardio side effects, and don't we just need to design molecules and do the preclinical and clinical testing?<< Yup. Do you think ACP-103 has been designed without a certain moiety (or something like that) that would cause cv effects, so that the reason we are not seeing them is not because the trials are small, but because they won't come up? That would be nice. To my knowledge, we haven't seen what the side effects were in murine models. Maybe one would if one paid for this article: Message 22165113 and maybe one wouldn't. How come so much animal data seems to be a secret? Because we investors might misinterpret it, or for competitive reasons? I remember one biofreak's (you probably remember who it is) comments years ago after watching a video presentation involving LEXG Alzheimer's mice that had been given a LEXG compound for Alzheimer's and were doing the swim test or a maze. One seemed to be swimming/turning in circles. I think it put him off the whole company, which as things are turning out, was the correct attitude. Hey, you can only take your Volvo so far down those forest roads. Get the Tacoma or whatever. Why should we stop you? It's not like you can't afford one; you probably daytrade your way to a new Tacoma every week. Concerned about the gas guzzling aspect? Aren't there some hybrids coming out? You might have to daytrade for two weeks for one of those . . . Cheers, Tuck

To: scaram(o)uche who wrote (360)	4/5/2007 1:29:13 PM
From: tuck	Read Replies (1) \| Respond to of 588

[In vitro pharmacology of clinically used CNS active drugs as inverse H1 receptor agonists] >>J Pharmacol Exp Ther. 2007 Apr 2; [Epub ahead of print] In vitro pharmacology of clinically used CNS active drugs as inverse H1 receptor agonists. Bakker RA, Nicholas MW, Smith TT, Burstein ES, Hacksell U, Timmerman H, Leurs R, Brann MR, Weiner DM. LACDR. The human histamine H1 receptor (H1R) is a prototypical G-protein coupled receptor (GPCR) and an important, well-characterised target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are also known to potently antagonise this receptor, underlying aspects of their side effect profiles. We have used the cell-based R-SAT assay to further define the clinical pharmacology of the human H1R by evaluating > 130 therapeutic and reference drugs for functional receptor activity. Based on this screen we have previously reported on the identification of 8R-lisuride as a potent stereospecific partial H1R agonist (Bakker et al, 2004, Mol. Pharmcol. 65:538-549). In contrast, herein we report on a large number of varied clinical and chemical classes of drugs that are active in the central nervous system (CNS) that display potent H1R inverse agonist activity. Absolute and rank order of functional potency of these clinically relevant brain-penetrating drugs may possibly be used to predict aspects of their clinical profiles, including propensity for sedation.<< LACDR is a Dutch research institute. Hacksell and Brann published with these guys in 2004. But if there is a program associated with it at Acadia, I can't find it. Kind of annoying that they don't have a pipeline chart at their website, so we don't know what's happening preclinically. Yet, we know that CNS-related inverse agonists are their game. This is a full text freebie, as is the predecessor work (in which the Acadia affiliation is noted): jpet.aspetjournals.org And the 2004 paper: molpharm.aspetjournals.org >>Mol Pharmacol. 2004 Mar;65(3):538-49. 8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist. Bakker RA, Weiner DM, ter Laak T, Beuming T, Zuiderveld OP, Edelbroek M, Hacksell U, Timmerman H, Brann MR, Leurs R. Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. ra.bakker@few.vu.nl The human histamine H1 receptor (H1R) is an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are known to potently antagonize the H1R, thereby producing some of their side effects. In contrast, the tolerability and potential therapeutic utility of H1R agonism is currently unclear. We have used a cell-based functional assay to evaluate known therapeutics and reference drugs for H1R agonist activity. Our initial functional screen identified three ergot-based compounds possessing heretofore-unknown H1R agonist activity. 8R-lisuride demonstrated potent agonist activity in various assays including receptor selection and amplification technology, inositol phosphate accumulation, and activation of nuclear factor-kappaB with pEC50 values of 8.1, 7.9, and 7.9, respectively, and with varying degrees of efficacy. Based on these assays, 8R-lisuride is the most potent stereospecific partial agonist for the human H1R yet reported. Investigation of the residues involved in histamine and lisuride binding, using H1R mutants and molecular modeling, have revealed that although these ligands are structurally different, the lisuride-binding pocket in the H1R closely corresponds to the histamine-binding pocket. The discovery of a potent stereospecific partial H1R agonist provides a valuable tool to further characterize this important therapeutic target in vitro.<< So they are apparently looking for an inverse agonist that will have the same neuropsychiatric effects as an antagonist, but without the side effects of antagonism. Or in any case, they are trying to sidestep the side effects, whether they have to antagonize or inverse agonize. Have I got that right? Cheers, Tuck