[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 |
