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Development and characterization of a highly selective M5 PAM probe molecule with improved potency.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2012 Dec 13 [updated 2013 Mar 22].

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Vanderbilt University
Scripps Research Institute.


Additional diversity-oriented exploration applied to our two previously disclosed, highly selective M5 Positive Allosteric Modulator (PAM) probes (ML129 and ML172) initially met with flat Structure-Activity-Relationship (SAR) and negligible improvements. Speculative incorporation of a novel fragment structure from the unconfirmed, single-point High Throughput Screen (HTS) effort concurrently underway at Scripps Research Institute Molecular Screening Center (SRIMSC) initiated a new series of compounds. SAR around this series provided, for the first time, sub-micromolar functional activity and ultimately led to the selection of ML326 as our 3rd generation M5 PAM probe molecule (hM5 PAM EC50 = 550 nM, hM1–4 > 30 μM, hM5 ACh fold-shift = 19). This best-in-class compound will find utility in assays directed toward understanding M5 receptor signaling both in vitro and, to a more limited extent, in vivo.

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