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Discovery of a Highly Selective in vitro and in vivo M4 Positive Allosteric Modulator (PAM) Series with Greatly Improved Human Receptor Activity.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2010 Aug 31 [updated 2013 Mar 14].


This probe (ML173, CID 45142486) can be used both in vitro and in vivo to study the role of selective M4 receptor activation. This probe possesses excellent selectivity versus M1, M2, M3 and M5, as well as a large panel of G-protein-coupled receptors (GPCRs), ion channels, and transporters. Moreover, this probe displays an order of magnitude greater potency at the human M4 receptor versus the rat M4 receptor (human M4 EC50 = 95 nM) surpassing our initial M4 positive allosteric modulator (PAM) probe, and now affects a large fold shift at both the human (60x) and rat (44x) receptors. While close analogs are active in rodent preclinical antipsychotic behavioral models, the greatly improved human potency may warrant testing in antipsychotic behavioral models with non-human primates. ML173 possess improved metabolic stability over the earlier M4 PAM probe (CID 864492) making it a potentially better in vivo tool.

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