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Markus Hierl, BaoXi Gao, Kristie Clarkin, Todd Juan, Hung Nguyen, Marissa van der Valk, Hong Deng, Wenhong Guo, Sonya Lehto, David Matson, Jeff McDermott, Johannes Knop, Kevin Gaida, Lei Cao, Dan Waldon, Brian Albrecht, Alessandro Boezio, Katrina Copeland, Jean-Christophe Harmange, Stephanie Springer, Annika Malmberg, Stefan McDonough

Amgen Research GmbH Regensburg/Germany, Department of Neuroscience, Department of Protein Science, Department of Inflammation, Department of PKDM, Department of Chemistry Research and Discovery, Amgen Inc, Cambridge/MA and Thousand Oaks/CA

Nicotinic acetylcholine receptors (nAChRs) are well known targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. Genes α2- α10 and β2- β4 encode nicotinic receptor subunits and are expressed in the nervous system. The α4β2 channel is the nAChR most widely expressed in the brain and agonism of this neuronal nAChR is the basis for current or potential treatments of several neurological disorders, including chronic pain and nicotine addiction. It has been particularly difficult to engineer agonists with functional selectivity for α4β2, since the orthosteric site of nicotinic receptors is highly conserved among various subtypes. Hence, we searched for positive modulators of α4β2, in hope to find compounds that potentiate the receptor and are selective against other nAChRs. In theory, positive modulators should increase receptor opening only in presence of ligand, and therefore avoid potential problems such as receptor up-regulation and/or desensitization associated with continual exposure to agonist. Utilizing fluorescent-based live cell assays we screened our sample collection for nAChR α4β2 potentiators. Herein we present on the discovery and characterization of a series of substituted piperidines which are CNS-penetrant α4 modulators useful for pharmacological profiling.

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