Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity
| Autor: | Carrie K. Jones, Jerri M. Rook, Meredith J. Noetzel, Zixiu Xiang, Colleen M. Niswender, P. Jeffrey Conn, Hyekyung P. Cho, Jason Manka, Rocco D. Gogliotti, Karen J. Gregory, Ya Zhou, F. Edward Dudek, Paige N. Vinson, Wendy A. Pouliot, Thomas M. Bridges, Shaun R. Stauffer, J. Scott Daniels, Craig W. Lindsley |
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| Rok vydání: | 2012 |
| Předmět: |
Agonist
Male Niacinamide medicine.drug_class Receptor Metabotropic Glutamate 5 Allosteric regulation Pharmacology Biology Hippocampus Article chemistry.chemical_compound Slice preparation Allosteric Regulation In vivo Seizures medicine Excitatory Amino Acid Agonists Animals Humans Excitatory Amino Acid Agonist Picolinic Acids Biological Psychiatry Dose-Response Relationship Drug Drug discovery Glutamate receptor Rats HEK293 Cells chemistry Metabotropic glutamate receptor Neuroscience |
| Zdroj: | Biological psychiatry. 73(6) |
| ISSN: | 1873-2402 |
| Popis: | Background Metabotropic glutamate receptor subtype 5 (mGlu 5 ) activators have emerged as a novel approach to the treatment of schizophrenia. Positive allosteric modulators (PAMs) of mGlu 5 have generated tremendous excitement and fueled major drug discovery efforts. Although mGlu 5 PAMs have robust efficacy in preclinical models of schizophrenia, preliminary reports suggest that these compounds may induce seizure activity. Prototypical mGlu 5 PAMs do not activate mGlu 5 directly but selectively potentiate activation of mGlu 5 by glutamate. This mechanism may be critical to maintaining normal activity-dependence of mGlu 5 activation and achieving optimal in vivo effects. Methods Using specially engineered mGlu 5 cell lines incorporating point mutations within the allosteric and orthosteric binding sites, as well as brain slice electrophysiology and in vivo electroencephalography and behavioral pharmacology, we found that some mGlu 5 PAMs have intrinsic allosteric agonist activity in the absence of glutamate. Results Both in vitro mutagenesis and in vivo pharmacology studies demonstrate that VU0422465 is an agonist PAM that induces epileptiform activity and behavioral convulsions in rodents. In contrast, VU0361747, an mGlu 5 PAMs optimized to eliminate allosteric agonist activity, has robust in vivo efficacy and does not induce adverse effects at doses that yield high brain concentrations. Conclusions Loss of the absolute dependence of mGlu 5 PAMs on glutamate release for their activity can lead to severe adverse effects. The finding that closely related mGlu 5 PAMs can differ in their intrinsic agonist activity provides critical new insights that is essential for advancing these molecules through clinical development for treatment of schizophrenia. |
| Databáze: | OpenAIRE |
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