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Selective KOP Receptor Antagonists: Probe 1.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2010 Feb 28 [updated 2010 Oct 4].


The specific aim of this project is to identify subtype specific small molecule antagonists of the human kappa opioid (KOP) receptor that represent different chemical scaffolds than the many existing potent and selective literature antagonists. Such antagonists have been shown to prevent reinstatement of drug taking behavior in animal paradigms thought to model relapse, however all current antagonists are long-acting and lead to tolerance due to poor pharmacological clearance. On the basis of antagonist assay paradigms utilized in this project (G protein coupling, ERK activation and beta-arrestin recruitment), it is hypothesized that the mode of action of the identified probe, ML140 (CID-3342390), is through reversible binding at the KOR site occupied by opiates. Thus, in this paradigm, opioid agonist-stimulation is blocked by increasing doses of the antagonist probe. These novel scaffolds for KOP receptor antagonists are of interest because they may be short acting and rapidly cleared, and therefore find utility in the treatment of drug abuse, depression, and chronic pain without tolerance and habituation.

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